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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, CLEANCHEM LABS as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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DEUCRAVACITINIB

July 13, 2021 6:45 am / 1 Comment on DEUCRAVACITINIB

DEUCRAVACITINIB

BMS-986165

CAS 1609392-27-9, C20H22N8O3, 425.46

6-(cyclopropanecarbonylamino)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

OriginatorBristol-Myers Squibb
ClassAmides; Aniline compounds; Anti-inflammatories; Antipsoriatics; Antirheumatics; Cyclopropanes; Ethers; Hepatoprotectants; Organic deuterium compounds; Pyridazines; Skin disorder therapies; Small molecules; Triazoles
Mechanism of ActionTYK2 kinase inhibitors

Phase IIIPlaque psoriasis
Phase IICrohn’s disease; Lupus nephritis; Psoriatic arthritis; Systemic lupus erythematosus; Ulcerative colitis
Phase IAutoimmune disorders
No development reportedInflammatory bowel diseases; Psoriasis

02 Jul 2021Bristol-Myers Squibb plans a phase I pharmacokinetics trial (In volunteers) in USA (PO, Tablet) in July 2021 (NCT04949269)
14 Jun 2021Bristol-Myers Squibb plans a phase III trial for Psoriatic arthritis (Treatment-naïve) in USA, Brazil, Colombia, Czech republic, Hungary, Italy, Mexico, Romania, Spain and Taiwan in July 2021 (NCT04908202) (EudraCT2020-005097-10)
02 Jun 2021Interim efficacy and adverse events data from the phase III POETYK-PSO-1 trial in Psoriatic psoriasis presented at the 22nd Annual Congress of the European League Against Rheumatism (EULAR-2021)

BMS , presumed to be in collaboration with Jinan University and Chinese Academy of Sciences , is developing deucravacitinib, a TYK2 inhibitor, for treating autoimmune diseases, primarily psoriasis. In July 2021, deucravacitinib was reported to be in phase 3 clinical development.

Deucravacitinib (BMS-986165) is a highly selective, orally bioavailable allosteric TYK2 inhibitor for the treatment of autoimmune diseases, which selectively binds to TYK2 pseudokinase (JH2) domain (IC₅₀=1.0 nM) and blocks receptor-mediated Tyk2 activation by stabilizing the regulatory JH2 domain. Deucravacitinib inhibits IL-12/23 and type I IFN pathways.

PAPER

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b00444

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.

Bristol Myers Squibb Presents Positive Data from Two Pivotal Phase 3 Psoriasis Studies Demonstrating Superiority of Deucravacitinib Compared to Placebo and Otezla® (apremilast)

04/23/2021.. https://news.bms.com/news/details/2021/Bristol-Myers-Squibb-Presents-Positive-Data-from-Two-Pivotal-Phase-3-Psoriasis-Studies-Demonstrating-Superiority-of-Deucravacitinib-Compared-to-Placebo-and-Otezla-apremilast/default.aspx

Significantly more patients treated with deucravacitinib achieved PASI 75 and sPGA 0/1 compared to patients treated with placebo and Otezla at Week 16, with an increased benefit versus Otezla at Week 24 and maintained through Week 52

Deucravacitinib was well tolerated with a low rate of discontinuation due to adverse events

Deucravacitinib is a first-in-class, oral, selective tyrosine kinase 2 (TYK2) inhibitor with a unique mechanism of action

Results presented as late-breaking research at the 2021 American Academy of Dermatology Virtual Meeting Experience

PRINCETON, N.J.–(BUSINESS WIRE)– Bristol Myers Squibb (NYSE:BMY) today announced positive results from two pivotal Phase 3 trials evaluating deucravacitinib, an oral, selective tyrosine kinase 2 (TYK2) inhibitor, for the treatment of patients with moderate to severe plaque psoriasis. The POETYK PSO-1 and POETYK PSO-2 trials, which evaluated deucravacitinib 6 mg once daily, met both co-primary endpoints versus placebo, with significantly more patients achieving Psoriasis Area and Severity Index (PASI) 75 response and a static Physician’s Global Assessment score of clear or almost clear (sPGA 0/1) after 16 weeks of treatment with deucravacitinib. Deucravacitinib was well tolerated with a low rate of discontinuation due to adverse events (AEs).

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20210423005134/en(Graphic: Business Wire)

Deucravacitinib demonstrated superior skin clearance compared with Otezla^®(apremilast) for key secondary endpoints in both studies, as measured by PASI 75 and sPGA 0/1 responses at Week 16 and Week 24. Findings include:

PASI 75 Response in POETYK PSO-1 and POETYK PSO-2:

At Week 16, 58.7% and 53.6% of patients receiving deucravacitinib achieved PASI 75 response, respectively, versus 12.7% and 9.4% receiving placebo and 35.1% and 40.2% receiving Otezla.
At Week 24, 69.0% and 59.3% of patients receiving deucravacitinib achieved PASI 75 response, respectively, versus 38.1% and 37.8% receiving Otezla.
Among patients who achieved PASI 75 response at Week 24 with deucravacitinib and continued treatment with deucravacitinib, 82.5% and 81.4%, respectively, maintained PASI 75 response at Week 52.

sPGA 0/1 Response in POETYK PSO-1 and POETYK PSO-2:

At Week 16, 53.6% and 50.3% of patients receiving deucravacitinib achieved sPGA 0/1 response, respectively, versus 7.2% and 8.6% receiving placebo and 32.1% and 34.3% receiving Otezla.
At Week 24, 58.4% and 50.4% of patients receiving deucravacitinib achieved sPGA 0/1 response, respectively, versus 31.0% and 29.5% receiving Otezla.

“In both pivotal studies, deucravacitinib was superior to Otezla across multiple endpoints, including measures of durability and maintenance of response, suggesting that deucravacitinib has the potential to become a new oral standard of care for patients who require systemic therapy and need a better oral option for their moderate to severe plaque psoriasis,” said April Armstrong, M.D., M.P.H., Associate Dean and Professor of Dermatology at the University of Southern California. “As many patients with moderate to severe plaque psoriasis remain undertreated or even untreated, it is also highly encouraging to see that deucravacitinib improved patient symptoms and outcomes to a greater extent than Otezla.”

Superiority of Deucravacitinib Versus Placebo and Otezla

Deucravacitinib demonstrated a robust efficacy profile, including superiority to placebo for the co-primary endpoints and to Otezla for key secondary endpoints. In addition to PASI 75 and sPGA 0/1 measures, deucravacitinib was superior to Otezla across both studies in multiple other secondary endpoints, demonstrating significant and clinically meaningful efficacy improvements in symptom burden and quality of life measures.

POETYK PSO-1 and POETYK PSO-2 Results at Week 16 and Week 24
Endpoint	POETYK PSO-1 (n=666)	POETYK PSO-2 (n=1,020)
Deucravacitinib6 mg(n=332)	Otezla30 mg(n=168)	Placebo(n=166)	Deucravacitinib6 mg(n=511)	Otezla30 mg(n=254)	Placebo(n=255)
*PASI 75^a**
Week 16	58.7%*^†	35.1%	12.7%	53.6%*^‡	40.2%	9.4%
Week 24	69.0%^†	38.1%	–	59.3%^†	37.8%	–
*sPGA 0/1^b**
Week 16	53.6%*^†	32.1%	7.2%	50.3%*^†	34.3%	8.6%
Week 24	58.4%^†	31.0%	–	50.4%^†	29.5%	–
(Scalp) ss-PGA 0/1^c
Week 16	70.8%*^†	39.1%	17.4%	60.3%*^†	37.3%	17.3%
Week 24	71.8%^†	42.7%	–	59.7%^‡	41.6%	–
PSSD-Symptoms CFB^d
Week 16	-26.7*^†	-17.8	-3.6	-28.3*^†	-21.1	-4.7
Week 24	-31.9^†	-20.7	–	-29.1^†	-21.4	–
DLQI 0/1^e
Week 16	40.7%*^†	28.6%	10.6%	38.0%*^†	23.1%	9.8%
Week 24	47.8%^‡	24.2%	–	41.8%^†	21.5%	–

^{*Co-primary endpoints for POETYK PSO-1 and POETYK PSO-2 were PASI 75 and sPGA 0/1 for deucravacitinib vs placebo at Week 16.}

^{a. PASI 75 is defined as at least a 75% improvement from baseline in Psoriasis Area and Severity Index (PASI) scores. *p<0.0001 vs placebo. †p<0.0001 vs Otezla. ‡p=0.0003 vs Otezla.}

^{b. sPGA 0/1 is defined as a static Physician’s Global Assessment (sPGA) score of clear or almost clear. *p<0.0001 vs placebo. †p<0.0001 vs Otezla.}

^{c. ss-PGA 0/1 is defined as a scalp-specific Physician’s Global Assessment (ss-PGA) score of clear or almost clear in those with ss-PGA of at least 3 (moderate) at baseline. POETYK PSO-1: *p<0.0001 vs placebo. †p<0.0001 vs Otezla. POETYK PSO-2: *p<0.0001 vs placebo. †p<0.0001 vs Otezla. ‡p=0.0002 vs Otezla.}

^{d. Change from baseline (CFB) in Psoriasis Symptoms and Signs Diary (PSSD) captures improvement in symptoms of itch, pain, stinging, burning and skin tightness in patient eDiaries. *p<0.0001 vs placebo. †p<0.0001 vs Otezla.}

^{e. Dermatology Life Quality Index (DLQI) 0/1 scores reflect no effect at all on patient’s life in patients with a baseline DLQI score of ≥2. POETYK PSO-1: *p<0.0001 vs placebo. †p=0.0106 vs Otezla. ‡p<0.0001 vs Otezla. POETYK PSO-2: *p<0.0001 vs placebo. †p<0.0001 vs Otezla.}

Safety and Tolerability

Deucravacitinib was well-tolerated and had a similar safety profile in both trials. At Week 16, 2.9% of 419 patients on placebo, 1.8% of 842 patients on deucravacitinib and 1.2% of 422 patients on Otezla experienced serious adverse events (SAEs) across both studies. The most common AEs (≥5%) with deucravacitinib treatment at Week 16 were nasopharyngitis and upper respiratory tract infection with low rates of headache, diarrhea and nausea. At Week 16, 3.8% of patients on placebo, 2.4% of patients on deucravacitinib and 5.2% of patients on Otezla experienced AEs leading to discontinuation. Across POETYK PSO-1 and POETYK PSO-2 over 52 weeks, SAEs when adjusted for exposure (exposure adjusted incidence per 100 patient-years [EAIR]) were 5.7 with placebo, 5.7 with deucravacitinib and 4.0 with Otezla. In the same timeframe across both studies, EAIRs for AEs leading to discontinuation were 9.4 with placebo, 4.4 with deucravacitinib and 11.6 with Otezla. No new safety signals were observed during Weeks 16‒52.

Across both Phase 3 trials, rates of malignancy, major adverse cardiovascular events (MACE), venous thromboembolism (VTE) and serious infections were low and generally consistent across active treatment groups. No clinically meaningful changes were observed in multiple laboratory parameters (including anemia, blood cells, lipids and liver enzymes) over 52 weeks.

“The findings from both studies affirm that deucravacitinib – a first-in-class, oral, selective TYK2 inhibitor with a unique mechanism of action that inhibits the IL-12, IL-23 and Type 1 IFN pathways –may become an oral treatment of choice for people living with psoriasis. We believe deucravacitinib has significant potential across a broad range of immune-mediated diseases, and we are committed to further advancing our expansive clinical program with this agent,” said Mary Beth Harler, M.D., head of Immunology and Fibrosis Development, Bristol Myers Squibb. “We are in discussions with health authorities with the goal of bringing this new therapy to appropriate patients as soon as possible. At Bristol Myers Squibb, we are committed to building an immunology portfolio that addresses pressing unmet needs that exist for those impacted by serious dermatologic conditions and other immune-mediated diseases, to ultimately deliver the promise of living a better life.”

These results are available as a late-breaking research presentation (Session S033 – Late-Breaking Research Abstracts) as part of the 2021 American Academy of Dermatology (AAD) Virtual Meeting Experience (VMX). Full results of both studies will be submitted to a medical journal for peer review. In November 2020 and February 2021, respectively, Bristol Myers Squibb announced positive topline results from POETYK PSO-1 and POETYK PSO-2.

Visit www.bms.com/media/medical-meetings/bms-at-aad-vmx.html for more information on Bristol Myers Squibb’s scientific approach and resources on psoriasis and immune-mediated diseases.

About Deucravacitinib

Deucravacitinib (pronounced doo-krav-a-sih-ti-nib) is a first-in-class, oral, selective tyrosine kinase 2 (TYK2) inhibitor with a unique mechanism of action. Deucravacitinib is the first and only TYK2 inhibitor in clinical studies across multiple immune-mediated diseases. Bristol Myers Squibb scientists designed deucravacitinib to selectively target TYK2, thereby inhibiting signaling of interleukin (IL)-12, IL-23 and Type 1 interferon (IFN), key cytokines involved in psoriasis pathogenesis. Deucravacitinib achieves a high degree of selectivity by uniquely binding to the regulatory, rather than the active, domain of TYK2, which is structurally distinct from the regulatory domains of Janus kinase (JAK) 1, 2 and 3. At therapeutic doses, deucravacitinib does not inhibit JAK1, JAK2 or JAK3. Due to the innovative design of deucravacitinib, Bristol Myers Squibb earned recognition with the 2019 Thomas Alva Edison Patent Award for the science underpinning the clinical development of deucravacitinib.

Deucravacitinib is being studied in multiple immune-mediated diseases, including psoriasis, psoriatic arthritis, lupus and inflammatory bowel disease. In addition to POETYK PSO-1 and POETYK PSO-2, Bristol Myers Squibb is evaluating deucravacitinib in three other Phase 3 studies in psoriasis: POETYK PSO-3 (NCT04167462); POETYK PSO-4 (NCT03924427); POETYK PSO-LTE (NCT04036435). Deucravacitinib is not approved for any use in any country.

About the Phase 3 POETYK PSO-1 and POETYK PSO-2 Studies

PrOgram to Evaluate the efficacy and safety of deucravacitinib, a selective TYK2 inhibitor (POETYK) PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751) are global Phase 3 studies designed to evaluate the safety and efficacy of deucravacitinib compared to placebo and Otezla^® (apremilast) in patients with moderate to severe plaque psoriasis. Both POETYK PSO-1, which enrolled 666 patients, and POETYK PSO-2, which enrolled 1,020 patients, were multi-center, randomized, double-blind trials that evaluated deucravacitinib (6 mg once daily) compared with placebo and Otezla (30 mg twice daily). POETYK PSO-2 included a randomized withdrawal and retreatment period after Week 24.

The co-primary endpoints of both POETYK PSO-1 and POETYK PSO-2 were the percentage of patients who achieved Psoriasis Area and Severity Index (PASI) 75 response and those who achieved static Physician’s Global Assessment (sPGA) score of 0 or 1 at Week 16 versus placebo. Key secondary endpoints of the trials included the percentage of patients who achieved PASI 75 and sPGA 0/1 compared to Otezla at Week 16 and other measures.

About Psoriasis

Psoriasis is a widely prevalent, chronic, systemic immune-mediated disease that substantially impairs patients’ physical health, quality of life and work productivity. Psoriasis is a serious global problem, with at least 100 million people worldwide impacted by some form of the disease, including around 14 million people in Europe and approximately 7.5 million people in the United States. Up to 90 percent of patients with psoriasis have psoriasis vulgaris, or plaque psoriasis, which is characterized by distinct round or oval plaques typically covered by silvery-white scales. Despite the availability of effective systemic therapy, many patients with moderate to severe psoriasis remain undertreated or even untreated and are dissatisfied with current treatments. People with psoriasis report an impact on their emotional well-being, straining both personal and professional relationships and causing a reduced quality of life. Psoriasis is associated with multiple comorbidities that may impact patients’ well-being, including psoriatic arthritis, cardiovascular disease, metabolic syndrome, obesity, diabetes, inflammatory bowel disease and depression.

About Bristol Myers Squibb

Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram.

Celgene and Juno Therapeutics are wholly owned subsidiaries of Bristol-Myers Squibb Company. In certain countries outside the U.S., due to local laws, Celgene and Juno Therapeutics are referred to as, Celgene, a Bristol Myers Squibb company and Juno Therapeutics, a Bristol Myers Squibb company.

Otezla^® (apremilast) is a registered trademark of Amgen Inc.

PATENT

WO-2021129467

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021129467&tab=FULLTEXT&_cid=P22-KR0K6X-17883-1

Novel crystalline polymorphic forms (CSI and CSII) of deucravacitinib (also known as BMS-986165), useful a tyrosine kinase 2 pseudokinase domain (TYK2) inhibitor for treating psoriasis, systemic lupus erythematosus, and Crohn’s disease.Tyrosine kinase 2 (TYK2) is an intracellular signal transduction kinase that can mediate interleukin-23 (IL-23), interleukin-12 (IL-12) and type I interferon (IFN) These cytokines are involved in inflammation and immune response.
BMS-986165 is the first and only new oral selective TYK2 inhibitor, clinically used to treat autoimmune and autoinflammatory diseases (such as psoriasis, psoriatic arthritis, lupus and inflammatory bowel disease, Crowe Graciousness, etc.). The results of a phase III clinical study of the drug announced in November 2020 showed that BMS-986165 has shown positive clinical effects in the treatment of moderate to severe plaque psoriasis. In addition, BMS-986165 also shows good therapeutic effects in the treatment of systemic lupus erythematosus and Crohn’s disease.
The chemical name of BMS-986165 is 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)benzene (Yl)amino)-N-(methyl-D3)pyridazine-3-carboxamide, the structural formula is shown below, and is hereinafter referred to as “compound I”:

The crystal form is a solid in which the compound molecules are arranged in a three-dimensional order in the microstructure to form a crystal lattice. The phenomenon of drug polymorphism refers to the existence of two or more different crystal forms of the drug. Because of different physical and chemical properties, different crystal forms of the drug may have different dissolution and absorption in the body, which in turn affects the clinical efficacy and safety of the drug to a certain extent. Especially for poorly soluble solid drugs, the crystal form will have a greater impact. Therefore, drug crystal form must be an important content of drug research and also an important content of drug quality control.
WO2018183656A1 discloses compound I crystal form A (hereinafter referred to as “crystal form A”) and a preparation method thereof. The crystalline form A disclosed in WO2018183656A1 is the only known free crystalline form of Compound I. The inventor of the present application repeated the preparation method disclosed in WO2018183656A1 to obtain and characterize the crystal form A. The results show that the crystal form A has poor compressibility and high adhesion. Therefore, there is still a need in the art to develop a compound I crystalline form with good stability, good compressibility, and low adhesion for the development of drugs containing compound I.
The inventor of the present application has paid a lot of creative work and unexpectedly discovered the crystalline form CSI of compound I and the crystalline form CSII of compound I provided by the present invention, which have advantages in physical and chemical properties, preparation processing performance and bioavailability, for example, There are advantages in at least one aspect of melting point, solubility, hygroscopicity, purification, stability, adhesion, compressibility, fluidity, dissolution in vivo and in vitro, and bioavailability, especially good physical and chemical stability and mechanical stability It has good performance, good compressibility, and low adhesion, which solves the problems existing in the prior art, and is of great significance to the development of drugs containing compound I.

PATENT

US9505748 , a family member of WO2014074661 .

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014074661

Preparation 1

Step l Int1

Step 2 Int2 Step 3 Int3 Step 4 Int4

Example 52

Step 1

[00219] To a solution of 2-methoxy-3-(l-methyl-lH-l ,2,4-triazol-3-yl)aniline (10.26 g, 50.2 mmol) and Int8 (10.5 g, 50.2 mmol) in THF (120 mL) was added lithium bis(trimethylsilyl)amide (LiHMDS, 1M in THF, 151 mL, 151 mmol) in a dropwise manner using a pressure equalized addition funnel. The reaction was run for 10 minutes after the completion of the addition and then quenched with HCl (1M aq., 126 mL, 126 mmol). The reaction was concentrated on a rotary evaporator until the majority of the THF was removed and a precipitate prevailed throughout the vessel. Water (-500 mL) was then added and the slurry sonicated for 5 minutes and stirred for 15 min. The solid was filtered off, rinsing with water and then air dried for 30 minutes. The powder was collected and dissolved in dichloromethane. The organic layer was washed with water and brine and then dried over sodium sulfate, filtered and concentrated to provide the product (12.5 g, 66% yield) (carried on as is). 1H NMR (400MHz, DMSO-d₆) δ 11.11 (s, 1H), 9.36 (s, 1H), 8.56 (s, 1H), 7.72 (dd, J=7.8, 1.6 Hz, 1H), 7.60 (dd, J=7.9, 1.5 Hz, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.19 (s, 1H), 3.95 (s, 3H), 3.72 (s, 3H). LC retention time 1.18 [E]. MS(E⁺) m/z: 377 (MH⁺).

Step 2

[00220] Intl3 (2.32 g, 6.16 mmol) and cyclopropanecarboxamide (1.048 g, 12.31 mmol) were dissolved in dioxane (62 mL) and Pd₂(dba)₃ (564 mg, 0.616 mmol), Xantphos (534 mg, 0.924 mmol) and cesium carbonate (4.01 g, 12.3 mmol) were added. The vessel was evacuated three times (backfilling with nitrogen) and then sealed and heated to 130 °C for 140 minutes. The reaction was filtered through CELITE® (eluting with ethyl acetate) and concentrated (on smaller scale this material could then be purified using preparative HPLC). The crude product was adsorbed onto CELITE® using dichloromethane, dried and purified using automated chromatography (100% EtOAc) to provide example 52 (1.22 g, 46% yield). 1H NMR (500MHz, chloroform-d) δ 10.99 (s, 1H), 8.63 (s, 1H), 8.18 (s, 1H), 8.10 (d, J=0.5 Hz, 2H), 7.81 (dd, J=7.9, 1.7 Hz, 1H), 7.51 (dd, J=7.9, 1.4 Hz, 1H), 7.33 – 7.20 (m, 7H), 4.01 (d, J=0.3 Hz, 3H), 3.82 (s, 3H), 1.73 -1.60 (m, 1H), 1.16 – 1.06 (m, 2H), 0.97 – 0.84 (m, 2H). LC retention time 6.84 [N]. MS(E⁺) m/z: 426 (MH⁺).

Example 53

[00221] To a homogeneous solution of Example 52 (50 mg, 0.12 mmol) in dichloromethane (3 mL) was added HCI (1M aq., 0.13 mL, 0.13 mmol) resulting in the solution turning yellow. The homogenous solution was concentrated down and then re-concentrated from dichloromethane twice to remove residual water, resulting in a white powder. The powder was suspended in dichloromethane and sonicated for 15 minutes, the powder was then collected via filtration, rinsing with dichloromethane to provide the corresponding HCI salt (38 mg, 70% yield). 1H NMR (500MHz, chloroform-d) δ 12.02 (s, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 8.01 (dd, J=7.9, 1.5 Hz, 1H), 7.57 (br. s., 1H), 7.52 -7.46 (m, 1H), 7.36 (t, J=7.9 Hz, 1H), 4.03 (s, 3H), 3.83 (s, 3H), 2.05 – 1.95 (m, 1H), 1.16 – 1.09 (m, 2H), 1.03 (dd, J=7.4, 3.6 Hz, 2H). LC retention time 0.62 [j]. MS(E⁺) m/z: 426 (MH⁺).

[00222] Compare to NMR of parent free base: 1H NMR (500MHz, chloroform-d) δ 10.99 (s, 1H), 8.63 (s, 1H), 8.18 (s, 1H), 8.10 (d, J=0.5 Hz, 2H), 7.81 (dd, J=7.9, 1.7 Hz, 1H), 7.51 (dd, J=7.9, 1.4 Hz, 1H), 7.33 – 7.20 (m, 7H), 4.01 (d, J=0.3 Hz, 3H), 3.82 (s, 3H), 1.73 – 1.60 (m, 1H), 1.16 – 1.06 (m, 2H), 0.97 – 0.84 (m, 2H).

////////////DEUCRAVACITINIB, phase 3, BMS-986165, BMS 986165, psoriasis, systemic lupus erythematosus, Crohn’s disease,

CNC(=O)C1=NN=C(C=C1NC2=CC=CC(=C2OC)C3=NN(C=N3)C)NC(=O)C4CC4

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Azeliragon

October 10, 2019 1:36 pm / Leave a comment

Azeliragon

C₃₂H₃₈ClN₃O₂, 532.1 g/mol

CAS 603148-36-3

TTP488

UNII-LPU25F15UQ

LPU25F15UQ

TTP-488; PF-04494700

3-[4-[2-butyl-1-[4-(4-chlorophenoxy)phenyl]imidazol-4-yl]phenoxy]-N,N-diethylpropan-1-amine

MOA：RAGE inhibitor

Indication：Alzheimer’s disease (AD)

Status：Phase III (Active), Dementia, Alzheimer’s type
Company：vTv Therapeutics (Originator)

Azeliragon

Azeliragon is in phase III clinical for the treatment of Alzheimer’s type dementia.

Azeliragon was originally by TransTech Pharma (now vTv Therapeutics), then licensed to Pfizer in 2006.

Pfizer discontinued the research in 2011, now vTv Therapeutics continues the further reaserch.

vTv Therapeutics (previously TransTech Pharma) is developing azeliragon, an orally active antagonist of the receptor for advanced glycation end products (RAGE), for the treatment of Alzheimer’s disease (AD) in patients with diabetes. In June 2019, this was still the case .

Azeliragon was originally developed at TransTech Pharma. In September 2006, Pfizer entered into a license agreement with the company for the development and commercialization of small- and large-molecule compounds under development at TransTech. Pursuant to the collaboration, Pfizer gained exclusive worldwide rights to develop and commercialize TransTech’s portfolio of RAGE modulators, including azeliragon.

Reference：

1. WO03075921A2.

2. US2008249316A1.

US 20080249316

VTV Therapeutics

Azeliragon (TTP488) is an orally bioavailable small molecule that inhibits the receptor for advanced glycation endproducts (RAGE). A Phase 2 clinical trial to evaluate azeliragon as a potential treatment of mild-AD in patients with type 2 diabetes is ongoing. The randomized, double-blind, placebo-controlled multicenter trial is designed as sequential phase 2 and phase 3 studies operationally conducted under one protocol. For additional information on the study, refer to NCT03980730 at Clinicaltrials.gov.

RAGE is an immunoglobulin-like cell surface receptor that is overexpressed in brain tissues of patients with AD. The multiligand nature of RAGE is highlighted by its ability to bind diverse ligands such as advanced glycation end-products (AGEs), linked to diabetic complications and β-amyloid fibrils, a hallmark of AD. The association between type 2 diabetes and AD is well documented. A linear correlation between circulating hemoglobin A1c (HbA1c) levels and cognitive decline has been demonstrated in the English Longitudinal Study of Ageing.

PATENT

WO-2019190823

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019190823&tab=PCTDESCRIPTION&_cid=P12-K1K59I-21476-1

Novel crystalline forms of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine and its salt ( azeliragon ) (deignated as forms III and IV) as RAGE inhibitors useful for treating psoriasis, rheumatoid arthritis and Alzheimer’s disease.

The Receptor for Advanced Glycation Endproducts (RAGE) is a member of the immunoglobulin super family of cell surface molecules. Activation of RAGE in different tissues and organs leads to a number of pathophysiological consequences. RAGE has been implicated in a variety of conditions including: acute and chronic inflammation (Hofmann et al., Cell 97:889-901 (1999)), the development of diabetic late complications such as increased vascular permeability (Wautier et al., J. Clin. Invest. 97:238-243 (1995)), nephropathy (Teillet et al., J. Am. Soc. Nephrol. 11 : 1488- 1497 (2000)), atherosclerosis (Vlassara et. al., The Finnish Medical Society DUODECIM, Ann. Med. 28:419-426 (1996)), and retinopathy (Hammes et al., Diabetologia 42:603-607 (1999)). RAGE has also been implicated in Alzheimer’s disease (Yan et al., Nature 382: 685-691 , (1996)), erectile dysfunction, and in tumor invasion and metastasis (Taguchi et al., Nature 405: 354-357, (2000)).

Binding of ligands such as advanced glycation endproducts (AGEs), S100/calgranulin/EN-RAGE, b-amyloid, CML (N^e-Carboxymethyl lysine), and amphoterin to RAGE has been shown to modify expression of a variety of genes. For example, in many cell types interaction between RAGE and its ligands generates oxidative stress, which thereby results in activation of the free radical sensitive transcription factor NF-kB, and the activation of NF-kB regulated genes, such as the cytokines IL- 1 b, TNF- a, and the like. In addition, several other regulatory pathways, such as those involving p21 ras.

MAP kinases, ERK1 and ERK2, have been shown to be activated by binding of AGEs and other ligands to RAGE. In fact, transcription of RAGE itself is regulated at least in part by NF-kB. Thus, an ascending, and often detrimental, spiral is fueled by a positive feedback loop initiated by ligand binding. Antagonizing binding of physiological ligands to RAGE, therefore, is our target, for down-regulation of the pathophysiological changes brought about by excessive concentrations of AGEs and other ligands for RAGE.

Pharmaceutically acceptable salts of a given compound may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, melting point, crystal shape, compaction behavior, flow properties, and/or solid state stability. These differences affect practical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability). Although U.S. Patent No. 7,884,219 discloses Form I and Form II of COMPOUND I as a free base, there is a need for additional drug forms that are useful for inhibiting RAGE activity in vitro and in vivo, and have properties suitable for large-scale manufacturing and formulation. Provided herein

PATENT

WO03075921

PATENT

WO2019190822

PATENT

WO2008123914

Publications

Links to the following publications and presentations, which are located on outside websites, are provided for informational purposes only and do not constitute the opinions or views of vTv Therapeutics

Presentations and Posters

///////////Azeliragon, psoriasis, rheumatoid arthritis, Alzheimer’s disease, TTP-488, PF-04494700, RAGE inhibitors, TransTech Pharma, PHASE 3, Dementia, Alzheimer’s type,

CCCCC1=NC(=CN1C2=CC=C(C=C2)OC3=CC=C(C=C3)Cl)C4=CC=C(C=C4)OCCCN(CC)CC

Benvitimod, Tapinarof, тапинароф , تابيناروف , 他匹那罗 ,

September 13, 2019 1:01 pm / Leave a comment

ChemSpider 2D Image | 3,5-Dihydroxy-4-isopropyl-trans-stilbene | C17H18O2

Benvitimod, Tapinarof

Molecular FormulaC₁₇H₁₈O₂
Average mass254.324 Da

3,5-dihydroxy-4-isopropyl-trans-stilbene

Launched – 2019 CHINA, Psoriasis, Tianji Pharma
тапинароф [Russian] [INN]WBI-1001

تابيناروف [Arabic] [INN]

他匹那罗 [Chinese] [INN]

(E)-2-(1-Methylethyl)-5-(2-phenylethenyl)-1,3-benzenediol

1,3-Benzenediol, 2-(1-methylethyl)-5-(2-phenylethenyl)-, (E)-

1,3-Benzenediol, 2-(1-methylethyl)-5-[(E)-2-phenylethenyl]-

10253

2-Isopropyl-5-[(E)-2-phenylvinyl]-1,3-benzenediol

3,5-Dihydroxy-4-isopropyl-trans-stilbene

5-[(E)-2-phenylethenyl]-2-(propan-2-yl)benzene-1,3-diol

79338-84-4 [RN]

84HW7D0V04

Research Code：WB-1001; WBI-1001

Trade Name：MOA：NSAID

Indication：Atopic dermatitis; PsoriasisStatus：

Phase III (Active)

Company：GlaxoSmithKline (Originator), Welichem Biotech (Originator), 天济药业 (Originator)

2894512
DMVT-505
GSK-2894512
RVT-505
WB-1001
WBI-1001
84HW7D0V04 (UNII code)

In May 2019, the drug was appoved in China for the treatment of moderate stable psoriasis vulgaris in adults and, in July 2019, Tianji Pharma (subsidiary of Guanhao Biotech) launched the product in China for the treatment of moderate stable psoriasis vulgaris in adults.

Benvitimod is in phase III clinical trials, Dermavant Sciences for the treatment of atopic dermatitis and psoriasis.

The compound was co-developed by Welichem Biotech and Stiefel Laboratories (subsidiary of GSK). However, Shenzhen Celestial Pharmaceuticals acquired the developement rights in China, Taiwan, Macao and Hong Kong.

Benvitimod (also known as Tapinarof or 3,5-dihydroxy-4-isopropyl-trans-stilbene) is a bacterial stilbenoid produced in Photorhabdus bacterial symbionts of Heterorhabditis nematodes.It is a product of an alternative ketosynthase-directed stilbenoids biosynthesis pathway. It is derived from the condensation of two β-ketoacyl thioesters. It is produced by the Photorhabdus luminescens bacterial symbiont species of the entomopathogenic nematode, Heterorhabditis megidis.

Benvitimod (also known as tapinarof or 3,5-dihydroxy-4-isopropyl-trans-stilbene) is a bacterial stilbenoid produced in Photorhabdus bacterial symbionts of Heterorhabditis nematodes. It is a product of an alternative ketosynthase-directed stilbenoids biosynthesis pathway. It is derived from the condensation of two β-ketoacyl thioesters .^[1] It is produced by the Photorhabdus luminescens bacterial symbiont species of the entomopathogenic nematode, Heterorhabditis megidis. Experiments with infected larvae of Galleria mellonella, the wax moth, support the hypothesis that the compound has antibiotic properties that help minimize competition from other microorganisms and prevents the putrefaction of the nematode-infected insect cadaver.^[2]

Tapinarof is a non-steroidal anti-inflammatory drug originated by Welichem Biotech. Dermavant Sciences is developing the product outside China in phase III clinical trials for the treatment of plaque psoriasis. The company is also conducting phase II clinical trials for the treatment of atopic dermatitis. Phase II studies had also been conducted by Welichem Biotech and Stiefel (subsidiary of GlaxoSmithKline) for these indications.

Tapinarof was originated at Welichem Biotech, from which Tianji Pharma and Shenzen Celestial Pharmaceuticals obtained rights to the product in the Greater China region in 2005. In 2012, Welichem licensed development and commercialization rights in all other regions to Stiefel. In 2013, Welichem entered into an asset purchase agreement to regain Greater China rights to the product from Tianji Pharma and Celestial; however, this agreement was terminated in 2014. In 2018, Stiefel transferred its product license to Dermavant Sciences.

Entomopathogenic nematodesemerging from a wax moth cadaver

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Medical research

Benvitimod is being studied in clinical trials for the treatment of plaque psoriasis.^[3]

PATENTS

Route 1

1. US2003171429A1.

2. US2005059733A1.

Route 2

Reference：1. CN103265412A.

Patent

https://patents.google.com/patent/CN103992212A/en

phenalkenyl Maude (Benvitimod) is a new generation of anti-inflammatory drugs, are useful for treating a variety of major autoimmune diseases, such as psoriasis, eczema, hair and more concentrated colitis allergic diseases.Phenalkenyl Maud stilbene compound, comprising cis and trans isomers, the trans alkenyl benzene Maude has a strong physiological activity, stability and physical and chemical properties, and cis alkenyl benzene Modesto predominantly trans phenalkenyl Maud byproducts during synthesis, conventional methods such as benzene alkenyl Maude Wittig reaction of cis-isomer impurity is inevitable.

[0004] benzyl trans-alkenyl Maude as main impurities in the synthesis, whether a drug is detected, or monitored during the reaction, the synthesis and analysis methods established cis alkenyl benzene Maude has very important significance.Phenalkenyl Maud conventional synthetic methods the impurity content is very low, and the properties of the cis compound is extremely unstable, easily converted to trans-structure, the synthetic method according to the preceding, the cis compound difficult to separate. The synthesis method has not been reported before in the literature. Thus, to find a synthesis route of cis-alkenyl benzene Maude critical.

[0005] The synthesis of compounds of cis-stilbene, in the prior art, there have been many reports, however, the prior art method of synthesizing a reaction product of the cis starting materials and reagents difficult source, the catalyst used is expensive higher costs, operational difficulties, is not conducive to large-scale production, such as:

① Gaukroger K, John A.Hadfield.Novel syntheses of cis and trans isomers ofcombretastatin A-4 [J] .J.0rg.Chemj 2001, (66): 8135-8138, instead of styrene and substituted phenyl bromide boric acid as the raw material, the Suzuki coupling reaction is a palladium catalyst, to give the cis compound, the reaction follows the formula:

Yield and selectivity of the process the structure is good, but the reaction is difficult source of raw materials, catalyst more expensive, limiting the use of this method.

[0006] ② Felix N, Ngassaj Erick A, Lindsey, Brandon Ej Haines.The first Cu- and

amine-free Sonogashira-type cross-coupling in the C_6 -alkynylation of protected

2, -deoxyadenosine [J] .Tetrahedron Letters, 2009, (65): 4085-4091, with a substituted phenethyl m

Alkynyl easily catalyst Pd / CaC03, Fe2 (CO) 9, Pd (OAc) 2 and the like produce cis compound to catalytic reduction. The reaction follows the formula:

Advantage of this method is stereospecific reduction of alkynes in the catalyst, to overcome the phenomenon of cis-trans isomerization of the Wittig reaction, but the reaction requires at _78 ° C, is not conducive to the operation, and the reagent sources difficult, expensive than high cost increase is not conducive to mass production.

[0007] ③ Belluci G, Chiappe C, Moro G L0.Crown ether catalyzed stereospecificsynthesis of Z_and E-stilbenes by Wittig reaction in a solid-liquid two-phasessystem [J] .Tetrahedron Letters, 1996, (37): 4225-4228 using Pd (PPh3) 4 as catalyst, an organic zinc reagent with a halide compound of cis-coupling reaction formula as follows:

The advantage of this method is that selective, high yield to give cis; deficiency is difficult to handle, the catalyst is expensive.

[0008] ④ new Wang, Zhangxue Jing, Zhou Yue, Zouyong Shun, trans-3,4 ‘, 5-trihydroxy-stilbene China Pharmaceutical Synthesis, 2005, 14 (4);. 204-208, reported that the trans compound of formula was dissolved in DMSO solution at a concentration dubbed, ultraviolet irradiation was reacted at 365nm, converted into cis compounds, see the following reaction formula:

However, the concentration of the solution preparation method, the reaction time is more stringent requirements.

Figure CN103992212AD00062

The synthesis of cis-alkenyl benzene Maude application embodiments Example 1 A synthesis of cis-alkenyl Maude benzene and benzene-cis-ene prepared Maude, the reaction was carried out according to the following scheme:

Specific preparation process steps performed in the following order:

(O methylation reaction

The 195.12g (Imol) of 3, 5-hydroxy-4-isopropyl benzoic acid, 414.57g (3mol) in DMF was added 5000ml anhydrous potassium carbonate, mixing, stirred at room temperature, then cooled in an ice-salt bath next, slowly added dropwise 425.85g (3mol) of iodomethane, warmed to room temperature after the addition was complete, the reaction 2h, after completion of the reaction was stirred with water, extracted with ethyl acetate, and concentrated to give 3,5-dimethoxy-4- isopropyl benzoate; yield 93%, purity of 99%.

[0033] (2) a reduction reaction

3000ml tetrahydrofuran and 240g (Imol) 3,5-dimethoxy-4-isopropyl benzoate, 151.40g (4mol) mixing at room temperature sodium borohydride was stirred and heated to reflux was slowly added dropwise 400ml methanol, reaction 4h, was added 3L of water was stirred, extracted with ethyl acetate, washed with water, the solvent was removed by rotary evaporation to give a white solid, to give 3,5-dimethoxy-4-isopropylbenzene methanol; 96% yield purity was 99%.

[0034] (3) the oxidation reaction

The 212g (ImoI) of 3,5-dimethoxy-4-isopropylbenzene methanol, DMSO 800ml and 500ml of acetic anhydride were mixed and stirred at rt After 2h, stirred with water, extracted with ethyl acetate, washed with water, dried , and concentrated to give 3,5-dimethoxy-4-isopropyl-benzaldehyde; 94% yield, 99% purity.

[0035] (4) a condensation reaction

The mixture was 209.18g (lmol) of 3,5-dimethoxy-4-isopropyl-benzoic awake and 136.15g (Imol) phenylacetic acid was added 5000ml of acetic anhydride, stirred to dissolve, sodium acetate was added 246.09g , heating to 135 ° C, the reaction after 6h, cooled to room temperature after adjusting the dilute acid 2 was added, extracted with ethyl acetate, the pH was concentrated, added saturated sodium bicarbonate solution adjusted to pH 7, stirred 2h, and extracted with dichloromethane , adding dilute aqueous hydrochloric acid pH 2, the yellow solid was filtered, to obtain 3,5-dimethoxy-4-isopropyl-stilbene acid; 96% yield, 80% purity.

[0036] (5) decarboxylation reaction

The 327g (Imol) of 3,5-dimethoxy-4-isopropyl-stilbene acid and 384g (6mol) of copper powder were added to 5000ml of quinoline, 180 ° C reaction 3h, cooled to room temperature ethyl acetate was added with stirring, filtered, and the filtrate was washed with dilute hydrochloric acid to the aqueous layer was colorless and the aqueous phase was extracted with ethyl acetate inverted, the organic layers were combined, washed with water and saturated brine until neutral, i.e., spin-dried to give 3,5 – dimethoxy-4-isopropyl-stilbene; 92% yield, 77% purity.

[0037] (6) Demethylation

The 282.32g (Imol) of 3,5-dimethoxy-4-isopropyl-stilbene 4000ml toluene was placed in an ice bath and stirring, was cooled to 0 ° C, and dissolved slowly added 605.9g (5mol after) in N, N- dimethylaniline, was added 666.7g (5mol) of anhydrous aluminum chloride. after stirring for 0.5h, warmed to room temperature, the reaction was heated to 100 ° C 2h, cooled to 60 ° C , hot toluene layer was separated, diluted hydrochloric acid was added to the aqueous phase with stirring to adjust the PH value of 2, extracted with ethyl acetate, washed with water, and concentrated to give the cis-alkenyl benzene Modesto; crude yield 95%, purity 74 %.After separation by column chromatography using 300-400 mesh silica gel, benzene-cis-ene was isolated Maude pure, 68% yield, 98.5% purity. The resulting cis-alkenyl benzene Maud NMR shown in Figure 1, NMR data are as follows:

1HNMR (CDCl3, 500 Hz, δ: ppm), 7.255 (m, 5H), 6.558 (d, 1H), 6.402 (d, 1H), 6.218 (s, 2H), 4.872 (s, 2H), 3.423 (m , 1H), 1.359 (q, 6H). Coupling constants / = 12.

[0038] trans-alkenyl benzene Maud NMR shown in Figure 2, the following NMR data:

1HNMR (CDCl3, 500 Hz, δ: ppm), 7.477 (d, 2H), 7.360 (t, 2H), 6.969 (q, 2H), 6.501 (s, 1H), 4.722 (s, 2H), 3.486 (m , 1H), 1.380 (t, 6H). Coupling constants / = 16.

[0039] HPLC conditions a cis alkenyl benzene Maude pure product: column was Nucleosil 5 C18; column temperature was 20 ° C; detection wavelength 318nm; mobile phase consisting of 50:50 by volume of acetonitrile and water; flow rate It was 0.6mL / min, injection volume of 5 μ L; cis phenalkenyl Maude 18.423min retention time of a peak in an amount of 96.39%, see Figure 3. Trans phenalkenyl Maude 17.630min retention time of a peak, the content was 99.8%, see Figure 4.After mixing the two, trans-alkenyl benzene Maude 17.664min retention time of the peak, cis-alkenyl benzene Maude 18.458min retention time of the peak, see Figure 5.

PATENT

https://patents.google.com/patent/CN103172497A/en

Figure CN103172497AC00021

phenalkenyl Maude is a natural product, a metabolite as to be symbionts.Phenalkenyl Maud Escherichia coli, Staphylococcus aureus has a very significant inhibitory effect, in addition, there is a styrenic Maude suppression of inflammation and its reactive derivative with immunomodulating activity. Alkenyl benzene Modesto topical ointment as an active ingredient, as a class of drugs has been completed two clinical treatment of psoriasis and eczema, the results of ongoing clinical phase III clinical studies, it has been shown to be completed in both psoriasis and eczema clearly effect, together with a styrenic Maude is a non-hormonal natural small molecule compounds, can be prepared synthetically prepared, therefore, it exhibits good market prospect.

[0004] a styrenic Maude initial synthesis route is as follows:

[0005]

[0006] The reaction conditions for each step: 1) isopropanol, 80% sulfuric acid, 60 ° C, 65% .2) sodium borohydride, boron trifluoride, tetrahydrofuran, 0 ° C, 90% .3). of thionyl chloride, heated under reflux, 85% .4). triethyl phosphate, 120 ° C, 80% .5). benzaldehyde, sodium hydride, 85% .6) pyridine hydrochloride, 190 ° C, 60 %.

[0007] The chemical synthesis route, although ultimately obtained a styrenic Maude, but the overall yield is low, part of the reaction step is not suitable for industrial production, due to process conditions result in the synthesis of certain byproducts produced is difficult to remove impurities, difficult to achieve the quality standard APIs.

Preparation of 4-isopropyl-dimethoxy-benzoic acid [0011] 1,3,5_

[0012] 1000 l reactor 200 liters of 80% sulfuric acid formulation (V / V), the temperature was lowered to room temperature, put 80 kg 3,5_-dimethoxybenzoate ,, stirring gradually warmed to 60 ° C, in was added dropwise within 25 kg of isopropanol I hour, the reaction was complete after 5 hours, 500 liters of hot water, filtered, the filter cake was washed with a small amount of hot water I th, crushed cake was removed and dried. The dried powder was recrystallized from toluene, the product was filtered to give 78 kg `, yield 86%. Preparation 2,3,5_ dimethoxy-4-isopropylbenzene methanol

[0013] 1000 l reactor was added 50 kg 3,5_ _4_ isopropyl dimethoxy benzoic acid, 24 kg of potassium borohydride, 400 l of THF, at room temperature was slowly added dropwise 65 kg BF3.Et2O was stirred 12 hours, the reaction was complete, pure water was added dropwise to destroy excess BF3, filtered, concentrated to dryness, methanol – water to give an off-white recrystallized 40.3 kg, yield 90.1%.

[0014] Preparation of 3,3,5-_ ■ methoxy _4- isopropyl group gas section

[0015] 1000 l autoclave, 100 kg of 3,5-dimethoxy-4-isopropylbenzene methanol, 220 l of DMF, 0 ° C and added dropwise with stirring and 50 l of thionyl chloride, 24 hours after the reaction was complete, 300 liters of water and 300 liters of ethyl acetate, the aqueous phase was stirred layered discharged, and then washed with 200 liters of water was added 3 times, until complete removal of DMF, was added concentrated crystallized from petroleum ether to give 98 kg of white solid was filtered and dried a yield of 91%.

Preparation of methyl-dimethoxy-4-isopropylbenzene of diethyl [0016] 4,3,5_

[0017] 500 l autoclave, 98 kg 3,5_ _4_ isopropyl dimethoxy benzyl chloride and 120 l of triethyl phosphite, the reaction at 120 ° C 5h, fear distilled off under reduced pressure, the collection 145-155 ° C / 4mmHg fear minutes, cured at room temperature to give a colorless light solid was 118 kg, yield 81.6%.

, 3- [0018] 5, E-1 _ ■ methoxy-2-isopropyl-5- (2-phenylethyl lean-yl) – benzene

[0019] 500 l autoclave, 33 kg 3,5_-dimethoxy-4-isopropylbenzene acid diethyl ester, 10.8 kg of benzaldehyde, and 120 l of tetrahydrofuran, at 40 ° C, and nitrogen with stirring, was added dropwise a solution of 11.8 kg potassium tert-butoxide in 50 liters of tetrahydrofuran, the temperature dropping control not to exceed 50 ° C. after the dropwise addition stirring was continued for I h, the reaction was complete, 150 liters of ethyl acetate and extracted , washed twice with 150 liters of water, 100 l I washed with brine, and the organic phase was dried and concentrated, methanol – water (I: D as a white crystalline solid 25.3 kg, yield 91%.

[0020] 6> 1, 3 ~ _ ■ Light-2-isopropyl-5- (2-phenylethyl lean-yl) – benzene (I), (De Dae dilute benzene)

[0021] 100 l autoclave, 10 kg 1,3_-dimethoxy-2-isopropyl-5- (2-styryl) benzene _ pyridine hydrochloride and 25 kg nitrogen atmosphere was heated to 180 -190 ° C, stirred for 3 hours after the reaction was completed, 20 l HCl (2N) cooling to 100 ° C, and 20 liters of ethyl acetate the product was extracted, dried and concentrated to give the product 7.3 kg, 83% yield.

[0022] The method for purifying:

[0023] 100 l added to the reaction vessel 15.5 kg of crude product and 39 liters of toluene, heated to the solid all dissolved completely, filtered hot and left to crystallize, after crystallization, filtration, the crystals with cold toluene 10 washed liter at 60 ° C, protected from light vacuo dried for 24 hours, to obtain 14 kg of white needle crystals, yield 90%.

CLIP

https://www.eosmedchem.com/article/237.html

Design new synthesis of Route of Benvitimod

Nov 26, 2018

1.Benvitimod and intermediates
Benvitimod 79338-84-4  intermediate： 1999-10-5
Benvitimod 79338-84-4  intermediate： 2150-37-0
Benvitimod 79338-84-4  intermediate： 344396-17-4
Benvitimod 79338-84-4  intermediate： 344396-18-5
Benvitimod 79338-84-4  intermediate： 344396-19-6
Benvitimod 79338-84-4  intermediate： 1080-32-6
Benvitimod 79338-84-4  intermediate： 678986-73-7
Benvitimod 79338-84-4  intermediate： 55703-81-6
Benvitimod 79338-84-4  intermediate： 1190122-19-0
Benvitimod 79338-84-4  intermediate： 443982-76-1
Benvitimod 79338-84-4  intermediate： 100-52-72.ROS-Benvitimod
(1)

(2)

3.
Name: Benvitimod
CAS#: 79338-84-4
Chemical Formula: C17H18O2
Exact Mass: 254.1307
Molecular Weight: 254.329
Elemental Analysis: C, 80.28; H, 7.13; O, 12.58

References

^ Joyce SA; Brachmann AO; Glazer I; Lango L; Schwär G; Clarke DJ; Bode HB (2008). “Bacterial biosynthesis of a multipotent stilbene”. Angew Chem Int Ed Engl. 47 (10): 1942–5. doi:10.1002/anie.200705148. PMID 18236486.
^ Hu, K; Webster, JM (2000). “Antibiotic production in relation to bacterial growth and nematode development in Photorhabdus–Heterorhabditis infected Galleria mellonella larvae”. FEMS Microbiology Letters. 189 (2): 219–23. doi:10.1111/j.1574-6968.2000.tb09234.x. PMID 10930742.
^ “New Topical for Mild to Moderate Psoriasis in the Works”. Medscape. March 5, 2017.
https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fanie.201814016&file=anie201814016-sup-0001-misc_information.pdf

///Benvitimod, Tapinarof, WBI-1001, тапинароф , تابيناروف , 他匹那罗 , Welichem Biotech, Stiefel Laboratories, Shenzhen Celestial Pharmaceuticals,CHINA 2019 , Psoriasis, Tianji Pharma, Dermavant Sciences, PHASE 3, fda 2022, approvals 2022, vtama, tapinarof

update….

5/23/2022 fda approved, To treat plaque psoriasis, vtama, tapinarof

Benvitimod
Names

Preferred IUPAC name 5-[(E)-2-Phenylethen-1-yl]-2-(propan-2-yl)benzene-1,3-diol
Other names (E)-3,5-Dihydroxy-4-isopropyl-trans-stilbene 3,5-Dihydroxy-4-isopropylstilbene
Identifiers
CAS Number	79338-84-4
3D model (JSmol)	Interactive image
ChemSpider	4943924
PubChem CID	6439522
UNII	84HW7D0V04
show InChI
show SMILES
Properties
Chemical formula	C₁₇H₁₈O₂
Molar mass	254.329 g·mol⁻¹
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Benvitimod (also known as tapinarof or 3,5-dihydroxy-4-isopropyl-trans-stilbene) is a bacterial stilbenoid produced in Photorhabdus bacterial symbionts of Heterorhabditis nematodes. It is a product of an alternative ketosynthase-directed stilbenoid biosynthesis pathway. It is derived from the condensation of two β-ketoacyl thioesters.^[1] It is produced by the Photorhabdus luminescens bacterial symbiont species of the entomopathogenic nematode, Heterorhabditis megidis. Experiments with infected larvae of Galleria mellonella, the wax moth, support the hypothesis that the compound has antibiotic properties that help minimize competition from other microorganisms and prevents the putrefaction of the nematode-infected insect cadaver.^[2]

Medical research

Benvitimod is being studied in clinical trials for the treatment of plaque psoriasis.^[3]

References

^ Joyce SA; Brachmann AO; Glazer I; Lango L; Schwär G; Clarke DJ; Bode HB (2008). “Bacterial biosynthesis of a multipotent stilbene”. Angew Chem Int Ed Engl. 47 (10): 1942–5. CiteSeerX 10.1.1.603.247. doi:10.1002/anie.200705148. PMID 18236486.
^ Hu, K; Webster, JM (2000). “Antibiotic production in relation to bacterial growth and nematode development in Photorhabdus–Heterorhabditis infected Galleria mellonella larvae”. FEMS Microbiology Letters. 189 (2): 219–23. doi:10.1111/j.1574-6968.2000.tb09234.x. PMID 10930742.
^ “New Topical for Mild to Moderate Psoriasis in the Works”. Medscape. March 5, 2017.

Tildrakizumab-asmn

June 1, 2018 8:14 am / Leave a comment

Heavy chain:
	QVQLVQSGAEVKKPGASVKVSCKASGYIFITYWMTWVRQAPGQGL
	EWMGQIFPASGSADYNEKFEGRVTMTTDTSTSTAYMELRSLRSDD
	TAVYYCARGGGGFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTS
	GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
	LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC
	PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
	EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
	KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL
	YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
	Light chain:
	DIQMTQSPSSLSASVGDRVTITCRTSENIYSYLAWYQQKPGKAPK
	LLIYNAKTLAEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQH
	HYGIPFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCL
	LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
	LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Tildrakizumab-asmn

Immunoglobulin G1, anti-(human interleukin 23) (human-Mus musculus monoclonal heavy chain), disulfide with human-Mus musculus monoclonal light chain, dimer

CAS 1326244-10-3, BLA 761067

Tildrakizumab (SCH 900222/MK-3222)

ILUMYA; MK-3222; SCH-900222; SUNPG 1622; SUNPG 1622 I; SUNPG 1623 I; SUNPG 1623 II; SUNPG 1623 III; SUNPG 1623 IV; SUNPG1623; Tildrakizumab-asmn

DRUG BANK https://www.drugbank.ca/drugs/DB14004

Company Sun Pharmaceuticals

Approval Status FDA Approved March 2018 FOR Psoriasis, plaque

Treatments plaque psoriasis

Protein chemical formulaC₆₄₂₆H₉₉₁₈N₁₆₉₈O₂₀₀₀S₄₆

Protein average weight144400.0 DaSequences

>Tildrakizumab Sequence
MLGSRAVMLLLLLPWTAQGRAVPGGSSPAWTQCQQLSQKLCTLAWSAHPLVGHMDLREEG
DEETTNDVPHIQCGDGCDPQGLRDNSQFCLQRIHQGLIFYEKLLGSDIFTGEPSLLPDSP
VGQLHASLLGLSQLLQPEGHHWETQQIPSLSPSQPWQRLLLRFKILRSLQAFVAVAARVF
AHGAATLSP

Tildrakizumab
Monoclonal antibody
Type	?
Source	Humanized (from mouse)
Target	IL23
Clinical data
Trade names	Ilumya
Synonyms	Tildrakizumab-asmn
Routes of administration	Subcutaneous injection
ATC code	none
Identifiers
CAS Number	1326244-10-3
ChemSpider	none
KEGG	D10400
Chemical and physical data
Formula	C₆₄₂₆H₉₉₁₈N₁₆₉₈O₂₀₀₀S₄₆
Molar mass	144.4 kg/mol

Originator Schering-Plough
Developer Almirall S.A.; Merck & Co; Schering-Plough; Sun Pharmaceutical Industries
Class Antipsoriatics; Monoclonal antibodies
Mechanism of Action Interleukin 23 inhibitors

Orphan Drug StatusNo
New Molecular EntityYes

Highest Development Phases

Registered Plaque psoriasis
Phase II Ankylosing spondylitis; Psoriatic arthritis
Discontinued Autoimmune disorders

Most Recent Events

21 Mar 2018 Registered for Plaque psoriasis in USA (SC) – First global approval
16 Feb 2018 Adverse events data from two phase III trials (reSURFACE 1 and 2) in chronic Plaque psoriasis presented at the 76^th Annual Meeting of the American Academy of Dermatology (AAD-2018)
16 Feb 2018 Pharmacokinetics data from population PK model in healthy volunteers and patients with psoriasis presented at the 76^th Annual Meeting of the American Academy of Dermatology (AAD-2018)

Ilumya (tildrakizumab-asmn) is an interleukin-23 antagonist.

Humanized monoclonal IgG1-kappa antibody against IL-23p19; produced in CHO cells
Immunoglobulin G1, anti-(human interleukin 23) (human-Mus musculus monoclonal heavy chain), disulfide with human-Mus musculus monoclonal light chain, dimer

Ilumya is specifically indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Ilumya is supplied as a solution for subcutaneous injection. The recommended dose is 100 mg at Weeks 0, 4, and every twelve weeks thereafter.

Image result for tildrakizumab-asmn

Tildrakizumab (Ilumya) is a monoclonal antibody designed for the treatment of immunologically mediated inflammatory disorders.^[1] In the United States, it is approved for the treatment of moderate-to-severe plaque psoriasis.^[2]

Tildrakizumab was designed to block interleukin-23, a cytokine that plays an important role in managing the immune system and autoimmune disease. Originally developed by Schering-Plough, this drug is now part of Merck‘s clinical program, following that company’s acquisition of Schering-Plough.

Sun Pharmaceutical acquired worldwide rights to tildrakizumab for use in all human indications from Merck in exchange for an upfront payment of U.S. $80 million. Upon product approval, Sun Pharmaceutical will be responsible for regulatory activities, including subsequent submissions, pharmacovigilance, post approval studies, manufacturing and commercialization of the approved product. ^[3]

Image result for tildrakizumab-asmn

As of March 2014, the drug was in phase III clinical trials for plaque psoriasis. The two trials enrolled nearly 2000 patients. ^[4]^[5]

In 2016, tildrakizumab became the first IL-23p19 inhibitor to demonstrate positive results in Phase-3 clinical trials for the treatment of moderate-to-severe plaque psoriasis, further validating the importance of the role of IL-23 in psoriasis. Sun Pharma signed a licensing pact with Spain’s Almirall for marketing tildrakizumab in Europe ^[6]

In March 2018, it was approved by the Food and Drug Administration for the treatment of moderate-to-severe plaque psoriasis as an injection for subcutaneous use in the United States.^[2]

In 2014, Sun Pharma acquired worldwide rights to tildrakizumab from Merck; upon product approval, Sun Pharma is responsible for regulatory activities, including subsequent submissions, pharmacovigilance, post approval studies, manufacturing and commercialization of the product. In 2016, Almirall sublicensed the product for the development and marketing in Europe for the treatment of psoriasis.

References

Mechanism of Action

Tildrakizumab is a humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines.

FDA APPROVAL DATA

BLA 761067

https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2018/761067Orig1s000REPLACEMENT_ltr.pdf

Please refer to your Biologics License Application (BLA) dated and received March 23, 2017 and your amendments, submitted under section 351(a) of the Public Health Service Act for ILUMYA (tildrakizumab-asmn) injection. We also refer to our approval letter dated March 20, 2018 which contained the following error: the Final Report Submission date was incorrectly listed for postmarketing requirement 3357-3. This replacement approval letter incorporates the correction of the error. The effective approval date will remain March 20, 2018, the date of the original approval letter.

LICENSING We have approved your BLA for ILUMYA (tildrakizumab-asmn) effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, ILUMYA under your existing Department of Health and Human Services U.S. License No. 0002. ILUMYA is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

MANUFACTURING LOCATIONS Under this license, you are approved to manufacture ILUMYA drug substance at . The final formulated drug product will be manufactured, filled, labeled, and packaged at MSD Ireland, Carlow, Ireland. You may label your product with the proprietary name, ILUMYA, and market it in 100 mg/1 mL single-dose prefilled syringe

DATING PERIOD The dating period for ILUMYA drug product shall be 36 months from the date of manufacture when stored at 2-8°C. The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product. The dating period for your drug substance shall be months from the date of manufacture when stored at We have approved the stability protocols in your license application for the purpose of extending the expiration dating period of your drug substance and drug product under 21 CFR 601.12.

PATENTS

WO 2014109927

PAPER

https://www.tandfonline.com/doi/full/10.4161/19420862.2015.988944

Tildrakizumab (SCH 900222/MK-3222) targets the p19 subunit of IL-23. The mAb was developed by Schering-Plough, which was acquired by Merck & Co. in 2009, and it was then licensed by Merck to Sun Pharmaceutical Industries Ltd in September 2014. Clinical development and regulatory activities will be conducted by Merck, but funded by Sun Pharma. As of October 2014, the safety and efficacy of tildrakizumab are being evaluated in 2 Phase 3 studies that are ongoing but not recruiting patients. Both studies include patients with moderate-to-severe chronic plaque psoriasis and subcutaneously administered drug. The 52-week Phase 3 NCT01729754 study has 4 arms (200 mg tildrakizumab; 100 mg tildrakizumab; 50 mg etanercept; and placebo only), and includes an optional long-term safety extension study. The estimated enrollment is 1050, and the estimated primary completion date is October 2019. The 64-week Phase 3 NCT01722331 study is evaluating the effects of either 200 mg or 100 mg tildrakizumab to placebo; it includes an optional long-term safety extension study. The estimated enrollment is 885, and the estimated primary completion date is June 2015.

Image result for tildrakizumab-asmn

Sun Pharma Announces U.S. FDA Approval of ILUMYA™ (tildrakizumab-asmn) for the Treatment of Moderate-to-Severe Plaque Psoriasis

NEWS PROVIDED BY

Sun Pharma

Mar 21, 2018, 09:04 ET

MUMBAI, India and PRINCETON, N.J., March 21, 2018 /PRNewswire/ — Sun Pharmaceutical Industries Ltd. (Reuters: SUN.BO, Bloomberg: SUNP IN, NSE: SUNPHARMA, BSE: 524715, “Sun Pharma” and includes its subsidiaries and/or associate companies) today announced that the U.S. Food and Drug Administration (FDA) has approved ILUMYA™ (tildrakizumab-asmn) for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. ILUMYA selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor leading to inhibition of the release of pro-inflammatory cytokines and chemokines. ILUMYA is administered at a dose of 100 mg by subcutaneous injection every 12 weeks, after the completion of initial doses at weeks 0 and 4. ILUMYA is contraindicated in patients with a previous serious hypersensitivity reaction to tildrakizumab or to any of the excipients.

“With the approval of ILUMYA and our long-standing commitment in dermatology, we are focused on making a difference for people living with moderate-to-severe plaque psoriasis,” said Abhay Gandhi, President and Chief Executive Officer, North America, Sun Pharma. “We are committed to working with all relevant stakeholders to make ILUMYA available to appropriate people with plaque psoriasis.”

The FDA approval of ILUMYA for the treatment of adults with moderate-to-severe plaque psoriasis was supported by data from the pivotal Phase-3 reSURFACE clinical development program. In the two multicenter, randomized, double-blind, placebo-controlled trials (reSURFACE 1 and reSURFACE 2), 926 adult patients were treated with ILUMYA (N=616) or placebo (N=310). Results from these studies were published in The Lancet in July 2017, with primary endpoints presented at the 25th European Academy of Dermatology and Venereology (EADV) Congress.

Both Phase-3 studies met the primary efficacy endpoints, demonstrating significant clinical improvement with ILUMYA 100 mg compared to placebo when measured by at least 75 percent of skin clearance (Psoriasis Area Sensitivity Index or PASI 75) and Physician’s Global Assessment (PGA) score of “clear” or “minimal” at week 12 after two doses.

*Efficacy Primary Endpoint at Week 12 in Adults with Plaque Psoriasis (NRI)**
	reSURFACE 1 Study (NCT01722331)		reSURFACE 2 Study (NCT01729754)
	ILUMYA 100 mg n=309	Placebo n=154	ILUMYA 100 mg n=307	Placebo n=156
PGA of “clear” (0) or “minimal” (1)†	179 (58%)	11 (7%)	168 (55%)	7 (4%)
PASI 75†	197 (64%)	9 (6%)	188 (61%)	9 (6%)
PASI 90	107 (35%)	4 (3%)	119 (39%)	2 (1%)
PASI 100	43 (14%)	2 (1%)	38 (12%)	0 (0%)

* NRI = Non-Responder Imputation † Co-Primary Endpoints

Of the patients in the reSURFACE 1 study 74 percent (229 patients) achieved 75 percent skin clearance at week 28 after three doses, and 84 percent of patients who continued receiving ILUMYA 100 mg maintained PASI 75 at week 64 compared to 22 percent of patients who were re-randomized to placebo. In addition, 69 percent of the patients receiving ILUMYA 100 mg who had a PGA score of “clear” or “minimal” at week 28 maintained this response at week 64 compared to 14 percent of patients who were re-randomized to placebo.

Full Prescribing Information and Medication Guide for ILUMYA are attached:
PDF: https://mma.prnewswire.com/media/656994/Sun_Pharma_ILUMYA_US_Prescribing_Information.pdf
PDF: https://mma.prnewswire.com/media/656995/Sun_Pharma_ILUMYA_US_Medication_Guide.pdf

IMPORTANT SAFETY INFORMATION (continued)

Cases of angioedema and urticaria occurred in ILUMYA treated subjects in clinical trial. If a serious hypersensitivity reaction occurs, discontinue ILUMYA immediately and initiate appropriate therapy.

ILUMYA may increase the risk of infection. Treatment with ILUMYA should not be initiated in patients with a clinically important active infection until the infection resolves or is adequately treated. Consider the risks and benefits of treatment prior to prescribing ILUMYA in patients with a chronic infection or a history of recurrent infection. Instruct patients receiving ILUMYA to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a clinically important or serious infection, or is not responding to standard therapy, closely monitor and discontinue ILUMYA until the infection resolves.

Evaluate patients for TB infection prior to initiating treatment with ILUMYA. Initiate treatment of latent TB prior to administering ILUMYA. Monitor patients for signs and symptoms of active TB during and after ILUMYA treatment. Do not administer ILUMYA to patients with active TB infection.

Prior to initiating ILUMYA, consider completion of all age-appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with ILUMYA.

The most common (≥1%) adverse reactions associated with ILUMYA include upper respiratory infections, injection site reactions, and diarrhea. Adverse reactions that occurred at rates less than 1% but greater than 0.1% in the ILUMYA group and at a higher rate than in the placebo group included dizziness and pain in extremity.

About the Phase-3 reSURFACE Trials
The Phase-3 studies (reSURFACE 1 and reSURFACE 2) were randomized, placebo-controlled, multicenter, three-part studies designed to demonstrate efficacy of ILUMYA in moderate-to-severe plaque psoriasis compared to placebo and comparative drug and to assess safety and tolerability. Part one of the studies randomized patients into three or four treatment arms, including ILUMYA 100 mg, ILUMYA 200 mg, placebo and etanercept (reSURFACE 2 only). After Week 12, patients on placebo were then re-randomized into ILUMYA 100 mg and 200 mg treatment arms to proceed into part two of the studies. Finally, in part three of the reSURFACE 1 study, responders (PASI ≥75) and partial responders (PASI ≥50 and PASI <75) to ILUMYA were re-randomized after Week 28 to continue the same treatment, a different dose of ILUMYA or placebo. Partial and non-responders to etanercept were treated with ILUMYA 200 mg in part three of the reSURFACE 2 study. Patients with guttate, erythrodermic, or pustular psoriasis were excluded.

About Psoriasis
Psoriasis is a chronic immune disease that appears on the skin. It is a non-contagious disorder that speeds the growth cycle of skin cells¹ and results in thick scaly areas of skin². The most common form, affecting about 80 to 90 percent of people living with psoriasis, is called plaque psoriasis³. It appears as red, raised areas of skin covered with flaky white scales, which may be itchy and painful and can crack and bleed². Many people with plaque psoriasis continue to struggle with the ongoing, persistent nature of this chronic disease.

About Sun Dermatology
Sun Dermatology (the branded dermatology division of a wholly owned subsidiary of Sun Pharma) is committed to expanding its dermatology portfolio to bring healthcare providers and patients around the world more treatment options and ongoing support for conditions like moderate-to-severe plaque psoriasis. Sun Pharma, along with its subsidiaries, is ranked fourth in dermatology prescription volume within the U.S. per IMS and is fifth largest specialty generic pharmaceutical company globally. In addition to ILUMYA, Sun Dermatology is comprised of several branded products indicated for the treatment of acne and actinic keratosis with a focus on other dermatologic conditions.

About Sun Pharma, Merck & Co., Inc., Kenilworth, NJ, USA, Agreement
Sun Pharmaceutical Industries Ltd.’s wholly owned subsidiary licensed worldwide rights to ILUMYA from a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, in 2014. Funded by a Sun Pharma subsidiary, Merck & Co., Inc., Kenilworth, NJ, USA was responsible for the completion of Phase-3 trials and submission of a Biologics License Application to the United States Food and Drug Administration (FDA), as well as manufacturing finished goods to support Sun Pharma’s initial product launch. Sun Pharma will be responsible for all post-approval regulatory activities, including subsequent submissions, pharmacovigilance, post approval studies, manufacturing and commercialization of the approved product. Sun Pharma will also be responsible for all regulatory, pharmacovigilance, post approval studies, manufacturing and commercialization of approved products for all non-U.S. markets. Merck & Co., Inc., Kenilworth, NJ, USA is eligible to receive milestone payments and royalties on sales of ILUMYA.

About Sun Pharma, Almirall S.A, Europe, Agreement
Sun Pharma and its wholly owned subsidiary and Almirall (Spanish Stock Exchange ticker: ALM) closed on July 2016 a licensing agreement on the development and commercialization of tildrakizumab-asmn for psoriasis in Europe. Under the terms of the licensing agreement, Almirall is able to lead European studies, and participate in larger Global clinical studies for plaque psoriasis indication subject to the terms of the Sun Pharma – Merck & Co., Inc., Kenilworth, NJ, USA agreements, as well as certain cost sharing agreements. Sun Pharma will be eligible to receive development and regulatory milestone payments and, additionally, sales milestone payments and royalties on net sales. Sun Pharma will continue to lead development of tildrakizumab-asmn for other indications, where Almirall will have right of first negotiation for certain indications in Europe. The agreement between Sun Pharma and Almirall remains subject to the exclusive licensing agreement between Sun Pharma and Merck & Co., Inc., Kenilworth, NJ, USA.

About Sun Pharmaceutical Industries Ltd. (CIN – L24230GJ1993PLC019050)
Sun Pharma is the world’s fifth largest specialty generic pharmaceutical company and India’s top pharmaceutical company. A vertically integrated business, economies of scale and an extremely skilled team enable us to deliver quality products in a timely manner at affordable prices. It provides high-quality, affordable medicines trusted by customers and patients in over 150 countries across the world. Sun Pharma’s global presence is supported by 41 manufacturing facilities spread across 6 continents, R&D centres across the globe and a multi-cultural workforce comprising over 50 nationalities. In India, the company enjoys leadership across 11 different classes of doctors with 30 brands featuring amongst top 300 pharmaceutical brands in India. Its footprint across emerging markets covers over 100 markets and 6 markets in Western Europe. Its Global Consumer Healthcare business is ranked amongst Top 10 across 3 global markets. Its API business footprint is strengthened through 14 world class API manufacturing facilities across the globe. Sun Pharma fosters excellence through innovation supported by strong R&D capabilities comprising about 2,000 scientists and R&D investments of approximately 8% of annual revenues. For further information, please visit www.sunpharma.com & follow us on Twitter @SunPharma_Live.

References
1. National Psoriasis Foundation. Facts about psoriasis. www.psoriasis.org/sites/default/files/for-media/MediaKit.pdf. Accessed on February 22, 2018.
2. National Psoriasis Foundation. About Psoriasis. www.psoriasis.org/about-psoriasis. Accessed on February 22, 2018.
3. Menter A, Gottlieb A, Feldman SR, Van Voorhees AS et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol 2008 May; 58(5):826-50.

////////////////tildrakizumab-asmn, FDA 2018, MERCK, Schering-Plough, MONOCLONAL ANTIBODY, SCH 900222, MK-3222, Psoriasis, plaque, BLA 761067, SCH-900222, SUNPG 1622, SUNPG 1622 I, SUNPG 1623 I, SUNPG 1623 II, SUNPG 1623 III, SUNPG 1623 IV, SUNPG1623,

Ponesimod

June 9, 2016 9:48 am / Leave a comment

Ponesimod

MW 460.97, C₂₃ H₂₅ Cl N₂ O₄ S

A sphingosine-1-phosphate receptor 1 (S1P1) agonist potentially for the treatment of multiple sclerosis.

(Z,Z)-5-[3-chloro-4-(2R)-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolylthiazolidin-4-one

(2Z,5Z)-5-[[3-Chloro-4-[(2R)-2,3-dihydroxypropoxy]phenyl]methylene]-3-(2-methylphenyl)-2-(propylimino)-4-thiazolidinone
5-[3-Chloro-4-[((2R)-2,3-dihydroxypropyl)oxy]benz-(Z)-ylidene]-2-((Z)-propylimino)-3-(o-tolyl)thiazolidin-4-one
ACT 128800

ACT-128800; RG-3477; R-3477

CAS No. 854107-55-4

update 18/3/21 FDA APPROVEDAS PONVORY

SYNTHESIS

Ponesimod

str1

NMR CDCL3 FROM NET

SEE……http://www.slideserve.com/truda/discovery-of-the-novel-orally-active-s1p-1-receptor-agonist-act-128800-ponesimod

Ponesimod (INN, codenamed ACT-128800) is an experimental drug for the treatment of multiple sclerosis (MS) and psoriasis. It is being developed by Actelion.

The first oral treatment for relapsing multiple sclerosis, the nonselective sphingosine-1-phosphate receptor (S1PR) modulator fingolimod, led to identification of a pivotal role of sphingosine-1-phosphate and one of its five known receptors, S1P₁R, in regulation of lymphocyte trafficking in multiple sclerosis. Modulation of S1P3R, initially thought to cause some of fingolimod’s side effects, prompted the search for novel compounds with high selectivity for S1P1R. Ponesimod is an orally active, selective S1P₁R modulator that causes dose-dependent sequestration of lymphocytes in lymphoid organs. In contrast to the long half-life/slow elimination of fingolimod, ponesimod is eliminated within 1 week of discontinuation and its pharmacological effects are rapidly reversible. Clinical data in multiple sclerosis have shown a dose-dependent therapeutic effect of ponesimod and defined 20 mg as a daily dose with desired efficacy, and acceptable safety and tolerability. Phase II clinical data have also shown therapeutic efficacy of ponesimod in psoriasis. These findings have increased our understanding of psoriasis pathogenesis and suggest clinical utility of S1P₁R modulation for treatment of various immune-mediated disorders. A gradual dose titration regimen was found to minimize the cardiac effects associated with initiation of ponesimod treatment. Selectivity for S1P₁R, rapid onset and reversibility of pharmacological effects, and an optimized titration regimen differentiate ponesimod from fingolimod, and may lead to better safety and tolerability. Ponesimod is currently in phase III clinical development to assess efficacy and safety in relapsing multiple sclerosis. A phase II study is also ongoing to investigate the potential utility of ponesimod in chronic graft versus host disease.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707431/

Biology and pharmacology of sphingosine-1-phosphate receptor 1

The past decades have witnessed major advances in the treatment of autoimmune and chronic inflammatory diseases. A plethora of novel therapies targeting specific molecules involved in the inflammatory or immune system activation cascades have become available. These have significantly increased our understanding of disease pathogenesis and improved the management of immune-mediated disorders. However, most of the targeted therapies are biological drugs which need to be injected, are eliminated slowly (e.g. over several weeks) and can lose efficacy or tolerability due to their potential immunogenicity. In an attempt to overcome these hurdles, pharmaceutical research has made considerable efforts to develop novel oral targeted therapies for autoimmune and chronic inflammatory diseases.

Sphingosine-1-phosphate receptor 1 (S1P₁R) is one of five known G protein-coupled receptors with nanomolar affinity for the lysophospholipid sphingosine-1-phosphate (S1P), which is generated through physiologic metabolism of the cell membrane constituent sphingomyelin by all cells [Brinkmann, 2007]. S1P receptors, including S1P₁R, are widely expressed in many tissues [Chun et al. 2010]. S1P₁R expression on lymphocytes controls their egress from thymus and secondary lymphoid organs [Cyster and Schwab, 2012]. Lymphocyte egress requires a gradient of S1P concentration, which is established by a high S1P concentration in blood and lymph compared with a low concentration in the interstitial fluid of lymphoid organs [Grigorova et al. 2009].

Synthetic S1P₁ receptor modulators disrupt the interaction of the physiologic S1P ligand with S1P₁R by promoting initial activation followed by sustained internalization and desensitization of S1P₁R [Hla and Brinkmann, 2011; Pinschewer et al. 2011]. Experiments conducted in animal models of transplant rejection, multiple sclerosis, lupus erythematosus, arthritis and inflammatory bowel disease with the first-generation, nonselective S1P receptor modulator, fingolimod, have demonstrated the potential efficacy of this mode of action across several immune-mediated chronic inflammatory conditions [Brinkmann, 2007]. Fingolimod is a structural analog of sphingosine that is phosphorylated in the body by a sphingosine kinase to generate the bioactive form of the drug, fingolimod phosphate, which binds to multiple S1P receptors [Brinkmann, 2007]. Clinical trials in multiple sclerosis (MS) have confirmed the efficacy of fingolimod in relapsing MS, but not in primary progressive disease, and led to the approval of the first oral medication for the treatment of relapsing forms of MS in 2010 [Kappos et al. 2010].

The mechanism of action of fingolimod has increased our understanding of MS pathogenesis. T and B cells, but not natural killer (NK) cells, express functional S1P₁R and are affected by fingolimod [Cyster and Schwab, 2012]. Furthermore, S1P₁R is differentially expressed and regulated in functionally distinct subsets of lymphocytes and fingolimod has been shown to predominantly affect naïve T cells and central memory T cells (T_CM) while sparing effector memory T cells (T_EM), and terminally differentiated effector T cells (T_E) in patients with relapsing MS [Mehling et al. 2008, 2011]. This has raised the possibility that, at least in MS, retention of T_CM cells, which include pro-inflammatory T helper 17 (Th17) cells, by fingolimod may prevent their accumulation in the cerebrospinal fluid (CSF) and subsequent differentiation to T_E cells in the central nervous system (CNS) [Hla and Brinkmann, 2011]. The effects of S1P₁R modulation on B cells are less well defined. Recent data from patients with relapsing MS have shown predominant reduction of memory B cells and recently activated memory B cells (CD38^int-high) in peripheral blood after treatment with fingolimod [Claes et al. 2014; Nakamura et al. 2014]. As memory B cells are implicated in the pathogenesis of MS and other autoimmune diseases, these observations suggest another potential mechanism underlying the therapeutic effects of S1P₁R modulators.

Astrocytes, microglia, oligodendrocytes and neurons express various S1P receptors including S1P₁R, S1P₃R and S1P₅R. Fingolimod has been shown to penetrate the CNS tissues and in vitro studies have shown activation of astrocytes and oligodendrocytes by fingolimod [Foster et al. 2007]. Conditional deletion of S1P₁R on neural cells in mice reduced the severity of experimental autoimmune encephalomyelitis (EAE) and reductions in the clinical scores were paralleled by decreased demyelination, axonal loss and astrogliosis [Choi et al. 2011]. Unfortunately, there was no beneficial effect in a recently completed, large study of fingolimod in patients with primary progressive MS [Lublin et al. 2015], suggesting that the direct effect on CNS cells alone may not be sufficient. Taken together, these data suggest the possibility of a direct beneficial effect of S1P₁R modulation in the brain of patients with relapsing MS [Dev et al. 2008]; however, its contribution to efficacy relative to the immunological effects remains unclear.

Initial studies in rodents suggested that modulation of S1P₃R on cardiac myocytes by fingolimod was associated with a reduction of heart rate (HR) by activation of G-protein-coupled inwardly rectifying potassium channels (GIRK) that regulate pacemaker frequency, and the shape and duration of action potentials [Koyrakh et al. 2005; Camm et al. 2014]. Modulation of S1P₂R and S1P₃R on myofibroblasts by fingolimod was also shown to stimulate extracellular matrix synthesis [Sobel et al. 2013]. Modulation of these receptors on vascular smooth muscle cells appeared to be associated with vasoconstriction, leading to the slight increase in blood pressure observed with fingolimod treatment [Salomone et al. 2003; Watterson et al. 2005; Hu et al. 2006; Lorenz et al. 2007; Kappos et al. 2010]. These observations raised the possibility that some side effects associated with fingolimod treatment could be avoided by more selective S1P₁R modulators, thus triggering the search for novel compounds.

Currently, there are several selective S1P₁R modulators in clinical development [Gonzalez-Cabrera et al.2014; Subei and Cohen, 2015]. Here we review data and the development status of ponesimod, a selective S1P₁R modulator developed by Actelion Pharmaceuticals Ltd.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707431/

Ponesimod, a selective, rapidly reversible, orally active, sphingosine-1-phosphate receptor modulator

Ponesimod (ACT-128800 (Z,Z)-5-[3-chloro-4-(2R)-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolylthiazolidin-4-one) is a selective, rapidly reversible, orally active, S1P₁R modulator. Ponesimod emerged from the discovery of a novel class of S1P₁R agonists based on the 2-imino-thiazolidin-4-one scaffold (Figure 1) [Bolli et al. 2010]. Ponesimod activates S1P₁R with high potency [half maximal effective concentration (EC50) of 5.7 nM] and selectivity. Relative to the potency of S1P, the potency of ponesimod is 4.4 higher for S1P₁R and 150-fold lower for S1P₃R, resulting in an approximately 650-fold higher S1P₁R selectivity compared with the natural ligand.

Figure 1.

Chemical structure of ponesimod, C₂₃H₂₅N₂O₄CIS (molecular weight 460.98).http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707431/

Clinical trials

In a 2009–2011 Phase II clinical trial including 464 MS patients, ponesimod treatment resulted in fewer new active brain lesions thanplacebo, measured during the course of 24 weeks.^[3]^[4]

In a 2010–2012 Phase II clinical trial including 326 patients with psoriasis, 46 or 48% of patients (depending on dosage) had a reduction of at least 75% Psoriasis Area and Severity Index (PASI) score compared to placebo in 16 weeks.^[3]^[5]

SEE https://clinicaltrials.gov/ct2/show/NCT02425644

Adverse effects

Common adverse effects in studies were temporary bradycardia (slow heartbeat), usually at the beginning of the treatment,dyspnoea (breathing difficulties), and increased liver enzymes (without symptoms). No significant increase of infections was observed under ponesimod therapy.^[3] QT prolongation is detectable but was considered to be too low to be of clinical importance in a study.^[6]

Mechanism of action

Like fingolimod, which is already approved for the treatment of MS, ponesimod blocks the sphingosine-1-phosphate receptor. This mechanism prevents lymphocytes (a type of white blood cells) from leaving lymph nodes.^[3] Ponesimod is selective for subtype 1 of this receptor, S1P₁.^[7]

PAPER

Bolli, Martin H.; Journal of Medicinal Chemistry 2010, V53(10), P4198-4211 CAPLUS

2-Imino-thiazolidin-4-one Derivatives as Potent, Orally Active S1P₁Receptor Agonists

Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland

J. Med. Chem., 2010, 53 (10), pp 4198–4211

DOI: 10.1021/jm100181s

Publication Date (Web): May 06, 2010

*To whom correspondence should be addressed. Phone: + 41 61 565 65 70. Fax: + 41 61 565 65 00. E-mail:martin.bolli@actelion.com.

Sphingosine-1-phosphate (S1P) is a widespread lysophospholipid which displays a wealth of biological effects. Extracellular S1P conveys its activity through five specific G-protein coupled receptors numbered S1P₁ through S1P₅. Agonists of the S1P₁ receptor block the egress of T-lymphocytes from thymus and lymphoid organs and hold promise for the oral treatment of autoimmune disorders. Here, we report on the discovery and detailed structure−activity relationships of a novel class of S1P₁ receptor agonists based on the 2-imino-thiazolidin-4-one scaffold. Compound 8bo (ACT-128800) emerged from this series and is a potent, selective, and orally active S1P₁ receptor agonist selected for clinical development. In the rat, maximal reduction of circulating lymphocytes was reached at a dose of 3 mg/kg. The duration of lymphocyte sequestration was dose dependent. At a dose of 100 mg/kg, the effect on lymphocyte counts was fully reversible within less than 36 h. Pharmacokinetic investigation of8bo in beagle dogs suggests that the compound is suitable for once daily dosing in humans.

(Z,Z)-5-[3-Chloro-4-((2R)-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolyl-thiazolidin-4-one (8bo)

…………..DELETED…………… column chromatography on silica gel eluting with heptane:ethyl acetate 1:4 to give the title compound (1.34 g, 37%) as a pale-yellow foam.

¹H NMR (CDCl₃): δ 0.94 (t, J = 7.3 Hz, 3 H), 1.58−1.70 (m, 2 H), 2.21 (s, 3 H), 3.32−3.48 (m, 2 H), 3.82−3.95 (m, 3 H), 4.12−4.27 (m, 4 H), 7.07 (d, J = 8.8 Hz, 1 H), 7.21 (d, J = 7.0 Hz, 1 H), 7.31−7.39 (m, 3 H), 7.49 (dd, J = 8.5, 2.0 Hz, 1 H), 7.64 (d, J= 2.0 Hz, 1 H), 7.69 (s, 1 H).

¹³C NMR (CDCl₃): δ 11.83, 17.68, 23.74, 55.42, 63.46, 69.85, 70.78, 133.48, 120.75, 123.71, 127.05, 128.25, 128.60, 129.43, 130.06, 131.13, 131.50, 134.42, 136.19, 146.98, 154.75, 166.12. LC-MS (ES⁺): t_R 0.96 min. m/z: 461 (M + H).

HPLC (ChiralPak AD-H, 4.6 mm × 250 mm, 0.8 mL/min, 70% hexane in ethanol): t_R 11.8 min. Anal. (C₂₃H₂₅N₂O₄SCl): C, H, N, O, S, Cl.

PATENT

WO 2014027330

https://www.google.com/patents/WO2014027330A1?cl=3Den

The present invention relates inter alia to a new process for the preparation of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (hereinafter also referred to as the “COMPOUND” or “compound (2)”), especially in crystalline form C which form is described in WO 2010/046835. The preparation of COMPOUND and its activity as immunosuppressive agent is described in WO 2005/054215. Furthermore, WO 2008/062376 describes a new process for the preparation of (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one which can be used as an intermediate in the preparation of COMPOUND.

Example 1 a) below describes such a process of preparing (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one according to WO 2008/062376. According to WO 2008/062376 the obtained (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one can then be transformed into COMPOUND by using standard methods for the alkylation of phenols. Such an alkylation is described in Example 1 b) below. Unfortunately, this process leads to the impurity (2Z,5Z)-5-(3-chloro-4-((1 ,3-dihydroxypropan-2-yl)oxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one which is present in about 2% w/w in the crude product (see Table 1 ) and up to 6 recrystallisations are necessary in order to get this impurity below 0.4% w/w (see Tables 1 and 2) which is the specified limit based on its toxicological qualification.

the obtained (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1 ) with 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one to form (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (2):

The reaction of (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1 ) with 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one can be performed under conditions which are typical for a Knoevenagel condensation. Such conditions are described in the literature for example in Jones, G., Knoevenagel Condensation in Organic Reaction, Wiley: New York, 1967, Vol. 15, p 204; or Prout, F. S., Abdel-Latif, A. A., Kamal, M. R., J. Chem. Eng. Data, 2012, 57, 1881-1886.

2-[(Z)-Propylimino]-3-o-tolyl-thiazolidin-4-one can be prepared as described in WO 2008/062376, preferably without the isolation and/or purification of intermediates such as the thiourea intermediate that occurs after reacting o-tolyl-iso-thiocyanate with n-propylamine. Preferably 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one obtained according to WO 2008/062376 is also not isolated and/or purified before performing the Knoevenagel condensation, i.e. before reacting 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one with (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1 ), i.e. in a preferred embodiment compound (2) is prepared in a one-pot procedure analogous to that described in WO 2008/062376.

Example 1 : (2Z,5Z)-5-(3-Chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one

a) Preparation of (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one:

Acetic acid solution: To acetic acid (149.2 mL) are added sodium acetate (1 1 .1 1 g, 2.00 eq.) and 3-chloro-4-hydroxybenzaldehyde (10.60 g, 1.00 eq.) at 20 °C. The mixture is stirred at 20 °C until complete dissolution (2 to 3 h).

n-Propylamine (4.04 g, 1.00 eq.) is added to a solution of o-tolyl-iso-thiocyanate (10 g, 1.00 eq.) in dichloromethane (100 mL) at 20 °C. The resulting pale yellow solution is agitated for 40 min at 20 °C before IPC (conversion specification≥ 99.0 %). The reaction is cooled to -2 °C. Bromoacetyl bromide (13.53 g, 1.00 eq.) is added and the resulting solution is stirred for 15 min at -2 °C. Pyridine (10.92 g, 2.05 eq.) is then added slowly at -2 °C. The intensive yellow reaction mixture is stirred for 15 min at -2 °C before IPC (conversion specification≥ 93.0 %). 70 mL of dichloromethane are distilled off under atmospheric pressure and jacket temperature of 60 °C. The temperature is adjusted to 42 °C and the acetic acid solution is added to the reaction mixture. The resulting solution is heated to 58 °C and stirred at this temperature for 15 h before IPC (conversion specification≥ 95 %). 25 mL of solvents are distilled off under vacuum 900 – 500 mbars and jacket temperature of 80 °C. The temperature is adjusted to 60 °C and water (80.1 mL) is added to the reaction mixture over 1 h. The resulting yellow suspension is stirred at 60 °C for 30 min. The suspension is cooled to 20 °C over 1 h and stirred at this temperature for 30 min.

The product is filtered and washed with a mixture of acetic acid (30 mL) and water (16 mL) and with water (50 mL) at 20 °C. The product is dried under vacuum at 50 °C for 40 h to afford a pale yellow solid; yield 25.93 g (78 %).

b) Preparation of crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:

To a suspension of (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one (10.00 g, 1.00 eq.) in ethanol (47.2 mL) is added (R)-3-chloro-1 ,2-

propanediol (3.37 g, 1.18 eq.) at 20 °C. Potassium tert-butoxide (3.39 g, 1.13 eq.) is added in portions at 20 °C. The resulting fine suspension is stirred at 20 °C for 25 min before being heated to reflux (88 °C). The reaction mixture is stirred at this temperature for 24 h before IPC (conversion specification≥ 96.0 %). After cooling down to 60 °C, acetonitrile (28.6 mL) and water (74.9 mL) are added. The resulting clear solution is cooled from 60 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.010 g, 0.001 eq.; crystalline form C can be prepared as described in WO 2010/046835) are added at 50 °C. The suspension is heated from 0 °C to 50 °C, cooled to 0 °C over 6 h and stirred at this temperature for 12 h.

The product is filtered and washed with a mixture of acetonitrile (23.4 mL) and water (23.4 mL) at 0 °C. The product is dried under vacuum at 45 °C for 24 h to afford a pale yellow solid; yield 1 1.91 g (84 %).

c) Purification of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:

Recrystallisation I: The crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (10 g) is dissolved in acetonitrile (30 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 12.8 mL).

Recrystallisation II: The wet product is dissolved in acetonitrile (27.0 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 1 1.3 mL).

Recrystallisation III: The wet product is dissolved in acetonitrile (24.3 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4- one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 10.1 mL).

Recrystallisation IV: The wet product is dissolved in acetonitrile (21.9 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 9.1 mL).

Recrystallisation V: The wet product is dissolved in acetonitrile (19.7 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 8.2 mL).

Recrystallisation VI: The wet product is dissolved in acetonitrile (23.9 mL) at 70 °C. Water (20 mL) is added at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h.

During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2- (propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed twice with a mixture of acetonitrile (4.5 mL) and water (4.5 mL) at -10 °C.

The product is dried under vacuum at 45 °C for 24 h to afford a pale yellow solid; yield: 7.0 g (70 %).

Example 2: (R)-3-Chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde

Potassium tert-butoxide (1 18 g, 1.20 eq.) is added to n-propanol (963 mL) followed by 3-chloro-4-hydroxybenzaldehyde (137 g, 1.00 eq.). To the mixture is added (R)-3-chloro-1 ,2-propanediol (126 g, 1.30 eq.). The suspension is heated to 90 °C and stirred at this temperature for 17 h. Solvent (500 mL) is distilled off at 120 °C external temperature and reduced pressure. Water is added (1.1 L) and solvent (500 mL) is removed by distillation. The turbid solution is cooled to 20 °C. After stirring for one hour a white suspension is obtained. Water (500 mL) is added and the suspension is cooled to 10 °C. The suspension is filtered and the resulting filter cake is washed with water (500 mL). The product is dried at 50 °C and reduced pressure to yield 149 g of a white solid (73%), which is (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde in crystalline form A.

Example 3: (R)-3-Chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde

Potassium tert-butoxide (8.60 g, 1.20 eq.) is added to n-propanol (70 mL) below 15 °C, the temperature is allowed to rise. After the addition the temperature is corrected again to below 15 °C before addition of 3-chloro-4-hydroxybenzaldehyde (10 g, 1 .00 eq.). The suspension is heated to 40 °C and stirred for 30 min. (R)-3-Chloro-1 ,2-propanediol (9.18 g, 1.30 eq.) is added at 40 °C. The resulting suspension is heated to 60 °C and stirred at this temperature for 15 h then heated to 94 °C till meeting the IPC-specification (specification conversion≥ 90.0 %). The mixture is cooled to 30 °C and n-propanol is partially distilled off (-50 mL are distilled off) under reduced pressure and a maximum temperature of 50 °C, the jacket temperature is not allowed to raise above 60 °C.

Water (81 mL) is added and a second distillation is performed under the same conditions (24 mL are distilled off). The mixture is heated till homogeneous (maximum 54 °C) and then cooled to 24 °C. At 24 °C the mixture is seeded with crystalline (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde of form A (0.013 g, 0.00085 eq.). How to obtain the crystalline seeds is described in Examples 2 and 5. The reaction mixture is cooled to 0 °C over 7.5 h.

The product is filtered and washed with water (2 x 35 mL) and once with methyl tert-butyl ether (20 mL) at 5 °C. The product is dried under vacuum at 40 °C for 20 h to afford an off-white solid; yield: 10.6 g (72 %), which is (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde in crystalline form A.

Example 4: (2Z,5Z)-5-(3-Chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)- 3-(o-tolyl)thiazolidin-4-one

a) Preparation of crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:

n-Propylamine (5.23 g, 1.32 eq.) is added to a solution of o-tolyl-iso-thiocyanate (10 g, 1.00 eq.) in dichloromethane (100 mL) at 20 °C. The resulting pale yellow solution is agitated for 15 min at 20 °C before IPC (conversion specification≥ 99.0 %). The reaction is cooled to -2 °C. Bromoacetyl bromide (14.88 g, 1.10 eq.) is added and the resulting solution is stirred for 15 min at -2 °C. Pyridine (10.92 g, 2.05 eq.) is then added slowly at -2 °C. The intensive yellow reaction mixture is stirred for 15 min at -2 °C before IPC (conversion specification≥ 93.0 %). Dichloromethane is partially distilled off (66 mL are distilled off) under atmospheric pressure and jacket temperature of 60 °C. Ethanol (1 1 1.4 mL), sodium acetate (12.75 g, 2.30 eq.) and (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde from Example 3 (14.38 g, 0.93 eq.) are added. The remaining dichloromethane and a part of ethanol are distilled off (49.50 mL are distilled off) under atmospheric pressure and jacket temperature up to 85 °C. The reaction mixture (orange suspension) is stirred for 3 – 5 h under reflux (78 °C) before IPC (conversion specification≥ 97.0 %).

Water (88.83 mL) is added and the temperature adjusted to 40 °C before seeding with micronized (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one in crystalline form C (0.075 g, 0.0024 eq.). The reaction mixture is cooled to 0 °C over 5 h, heated up to 40 °C, cooled to 0 °C over 6 h and stirred at this temperature for 2 h.

The product is filtered and washed with a 1 :1 ethanohwater mixture (2 x 48 mL) at 0 °C. The product is dried under vacuum at 45 °C for 10 h to afford a pale yellow solid; yield: 24.71 g (86 %).

b) Purification of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:

The crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (10 g) is dissolved in ethanol (40 mL) at 70 °C. The temperature is adjusted at 50 °C for seeding with micronised (2Z,5Z)-5-(3-chloro-4-((R)-2,3- dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one in crystalline form C (0.016 g, 0.0016 eq.). The reaction mixture is cooled from 50 °C to 0 °C over 4 h, heated up to 50 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h.

The product is filtered and washed with ethanol at 0 °C (2 x 12.8 mL). The product is dried under vacuum at 45 °C for 10 h to afford a pale yellow solid; yield: 9.2 g (92 %).

Example 5: Preparation of crystalline seeds of (R)-3-chloro-4-(2,3-dihydroxypropoxy)- benzaldehyde

10 mg of (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde of at least 99.5% purity by 1 H-NMR assay is dissolved in a 4 mL vial by adding 1 mL of pure ethanol (puriss p. a.). The solvent is allowed to evaporate through a small hole in the cap (approx. 2 mm of diameter) of the vial until complete dryness. The white solid residue is crystalline (R)-3-chloro-4-(2,3- dihydroxypropoxy)-benzaldehyde in crystalline form A. Alternatively, methanol or methylisobutylketone (both in puriss p. a. quality) is used. This procedure is repeated until sufficient seeds are made available.

PATENT

WO 2005054215

SEE https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2005054215

WO2005054215A1	Nov 16, 2004	Jun 16, 2005	Actelion Pharmaceuticals Ltd	5-(benz- (z) -ylidene) -thiazolidin-4-one derivatives as immunosuppressant agents
WO2008062376A2	Nov 22, 2007	May 29, 2008	Actelion Pharmaceuticals Ltd	New process for the preparation of 2-imino-thiazolidin-4-one derivatives
WO2010046835A1	Oct 19, 2009	Apr 29, 2010	Actelion Pharmaceuticals Ltd	Crystalline forms of (r) -5- [3-chloro-4- ( 2, 3-dihydroxy-propoxy) -benz [z] ylidene] -2- ( [z] -propylimino) -3-0-tolyl-thiazolidin-4-one

Reference
1	*	BOLLI, M.H. ET AL.: “2-Imino-thiazolidin-4-one Derivatives as Potent, Orally Active S1P1 Receptor Agonists“, JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, no. 10, 2010, pages 4198-4211, XP55090073, ISSN: 0022-2623, DOI: 10.1021/jm100181s

References

“Multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator: Favorable impact of dose up-titration”. The Journal of Clinical Pharmacology 54: 179–88. Feb 2014. doi:10.1002/jcph.244. PMID 24408162.
“Mass balance, pharmacokinetics and metabolism of the selective S1P1 receptor modulator ponesimod in humans”. Xenobiotica 45: 139–49. Feb 2015. doi:10.3109/00498254.2014.955832. PMID 25188442.
H. Spreitzer (29 September 2014). “Neue Wirkstoffe – Ponesimod”. Österreichische Apothekerzeitung (in German) (20/2014): 42.
“Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial”. Journal of Neurology, Neurosurgery 85: 1198–208. Nov 2014. doi:10.1136/jnnp-2013-307282. PMC 4215282. PMID 24659797.
“Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial”. The Lancet 384: 2036–45. Dec 2014. doi:10.1016/S0140-6736(14)60803-5. PMID 25127208.
“Effect of Ponesimod, a selective S1P1 Receptor Modulator, on the QT Interval in Healthy Subjects”. Basic 116: 429–37. May 2015.doi:10.1111/bcpt.12336. PMID 25287214.
“Ponesimod”. Actelion. Retrieved 31 October 2014.

ABOUT PONESIMOD

Ponesimod is a potent orally active, selective sphingosine-1-phosphate receptor 1 (S1P₁) immunomodulator.

Ponesimod prevents lymphocytes from leaving lymph nodes, thereby reducing circulating blood lymphocyte counts and preventing infiltration of lymphocytes into target tissues. The lymphocyte count reduction is rapid, dose-dependent, sustained upon continued dosing, and quickly reversible upon discontinuation. Initial data suggest that ponesimod does not cause lymphotoxicity by destroying/depleting lymphocytes or interfering with their cellular function. Other blood cells e.g. cells of the innate immune system are largely unaffected. Ponesimod is therefore considered a promising new oral agent for the treatment of a variety of autoimmune disorders.

CURRENT STATUS

OPTIMUM (Oral Ponesimod versus Teriflunomide In relapsing MUltiple sclerosis) is a Phase III multi-center, randomized, double-blind, parallel-group, active-controlled superiority study to compare the efficacy and safety of ponesimod to teriflunomide in patients with relapsing multiple sclerosis (RMS). The study aims to determine whether ponesimod is more efficacious than teriflunomide in reducing relapses. The study is expected to enroll approximately 1’100 patients, randomized in 2 groups in a 1:1 ratio to receive ponesimod 20 mg/day or teriflunomide 14 mg/day, and is expected to last a little over 3 years. An additional study to further characterize the utility and differentiation of ponesimod in multiple sclerosis is being discussed with Health Authorities.

Ponesimod is also evaluated in a Phase II open-label, single-arm, intra-subject dose-escalation study to investigate the biological activity, safety, tolerability, and pharmacokinetics of ponesimod in patients suffering from moderate or severe chronic graft versus host disease (GvHD)inadequately responding to first- or second-line therapy. The study will also investigate the clinical response to ponesimod treatment in these patients. Approximately 30 patients will be enrolled to receive ponesimod in escalating doses of 5, 10, and 20 mg/day over the course of 24 weeks. The study is being conducted at approximately 10 sites in the US and is expected to last approximately 18 months.

AVAILABLE CLINICAL DATA

The decision to move into Phase III development was based on the Phase IIb dose-finding study with ponesimod in patients with relapsing-remitting multiple sclerosis. A total of 464 patients were randomized into this study and the efficacy, safety and tolerability of three ponesimod doses (10, 20, and 40 mg/day) versus placebo, administered once daily for 24 weeks.

The primary endpoint of this study was defined as the cumulative number of new gadolinium-enhancing lesions on T1-weighted magnetic resonance imaging (MRI) scans at weeks 12, 16, 20, and 24 after study drug initiation. A key secondary endpoint of this study was the annualized relapse rate over 24 weeks of treatment. Patients who completed 24 weeks of treatment were offered the opportunity to enter into an extension study. This ongoing trial is investigating the long-term safety, tolerability, and efficacy of 10 and 20 mg/day of ponesimod in patients with relapsing-remitting multiple sclerosis, in a double-blind fashion. The study continues to provide extensive safety and efficacy information for ponesimod in this indication, with some patients treated for more than 6 years.

The safety database from all studies with ponesimod now comprises more than 1,300 patients and healthy volunteers.

MILESTONES

2015 – Phase III program in multiple sclerosis initiated
2011 – Phase IIb dose-finding study in multiple sclerosis successfully completed
2006 – Entry-into-man
2004 – Preclinical development initiated

KEY SCIENTIFIC LITERATURE

Olsson T et al. J Neurol Neurosurg Psychiatr. 2014 Nov;85(11):1198-208. doi: 10.1136/jnnp-2013-307282. Epub 2014 Mar 21

Freedman M.S, et al. Multiple Sclerosis Journal, 2012; 18 (4 suppl): 420 (P923).

Fernández Ó, et al. Multiple Sclerosis Journal, 2012; 18 (4 suppl): 417 (P919).

Piali L, Froidevaux S, Hess P, et al. J Pharmacol Exp Ther 337(2):547-56, 2011

Bolli MH, Abele S, Binkert C, et al. J Med Chem. 53(10):4198-211, 2010

Kappos L et al. N Engl J Med. 362(5):387-401, 2010

Ponesimod
Systematic (IUPAC) name


(2Z,5Z)-5-{3-Chloro-4-[(2R)-2,3-dihydroxypropoxy]benzylidene}-3-(2-methylphenyl)-2-(propylimino)-1,3-thiazolidin-4-one
Clinical data
Routes of administration	Oral
Legal status
Legal status	Investigational
Pharmacokinetic data
Metabolism	2 main metabolites
Biological half-life	31–34 hrs^[1]
Excretion	Feces (57–80%, 26% unchanged), urine (10–18%)^[2]
Identifiers
CAS Number	854107-55-4
ATC code	none
PubChem	CID 11363176
ChemSpider	9538103
ChEMBL	CHEMBL1096146
Synonyms	ACT-128800
Chemical data
Formula	C₂₃H₂₅ClN₂O₄S
Molar mass	460.974 g/mol

////Ponesimod, , A sphingosine-1-phosphate receptor 1, S1P1 agonist, multiple sclerosis. ACT-128800; RG-3477; R-3477, autoimmune disease, lymphocyte migration, multiple sclerosis, psoriasis, transplantation

CCC/N=C\1/N(C(=O)/C(=C/C2=CC(=C(C=C2)OC[C@@H](CO)O)Cl)/S1)C3=CC=CC=C3C

крисаборол , كريسابورول , Crisaborole, AN 2728

October 30, 2015 8:59 am / 1 Comment on крисаборол , كريسابورول , Crisaborole, AN 2728

Crisaborole

Treatment for Inflammatory Skin Diseases, including Atopic Dermatitis and Psoriasis

C₁₄H₁₀BNO_3,Average mass251.045 Da

4-[(1-Hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile ,

4-((1-Hydroxy-1,3-dihydrobenzo(c)(1,2)oxaborol-6-yl)oxy)benzonitrile

CAS 906673-24-3, AN-2728

Benzonitrile, 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]-

1,3-Dihydro-1-hydroxy-5-(4-cyanophenoxy)-2,1-benzoxaborole

5-(4-Cyanophenoxy)-l, 3-dihydro-l-hydroxy-2, 1-benzoxaborole

crisaborol, crisaborole, Crisaborole, crisaborolum

UNII-Q2R47HGR7P

крисаборол

كريسابورول

In phase 3 for treatment of mild to moderate atopic dermatitis……Anacor Pharmaceuticals, Inc.

Psoriasis is a chronic skin disorder caused by inflammatory cell infiltration into the dermis and epidermis, and is accompanied by keratinocyte hyperproliferation. Once triggered, a strong T-cell response is mounted, and a cascade of cytokine and chemokine production is induced.

Down-regulation of certain cytokines and chemokines is considered to be a good approach to treatment, and indeed, the biologics targeting TNF-α demonstrate the effectiveness of this approach.However, biologics have intrinsic challenges, such as limited administration route, side effects, quality control and production cost.

Small molecule approaches to treat psoriasis include systemic or topical steroids, cyclosporine, psoralen plus UVA (PUVA), retinoids, methotrexete, and vitamin D₃ analogs.Atopic dermatitis is an allergic skin disorder, which is typically treated with topical steroids, antihistamines, and calcineurin inhibitors.

However, there is still a need for new treatment with improved safety profile. Recently phosphodiesterase 4 (PDE4) inhibitors have been in development for such skin diseases. CC-10004 is in development as an oral treatment for psoriasis and atopic dermatitis. AWD-12-281 was, until recently, in development for the topical treatment of atopic dermatitis. In addition, roflumilast is under Phase 1 development for both diseases.

Figure 1.

PDE4 inhibitors aiming at skin inflammatory diseases.

Anacor’s lead product candidate is crisaborole, an investigational non-steroidal topical PDE-4 inhibitor in development for the potential treatment of mild-to-moderate atopic dermatitis and psoriasis

crisaborole is an investigational topical antiinflammatory drug in phase III clinical development by Anacor Pharmaceuticals for the treatment of mild to moderate atopic dermatitis and in phase II clinical trials in mild to moderate psoriasis

A novel boron-containing small molecule, Crisaborole inhibits the release of pro-inflammatory cytokines including TNF-alpha, IL-12, and IL-23, known mediators of the inflammation associated with psoriasis.

Synthesis

CKICK ON IMAGE FOR CLEAR VIEW

Originator

Anacor Pharmaceuticals

Therapeutic Claim

Inflammatory skin diseases

Atopic dermatitis

Psoriasis

Class

Nonsteroidal anti-inflammatories

Mechanism of action

Tumour necrosis factor alpha inhibitors

Type 4 cyclic nucleotide phosphodiesterase inhibitors

WHO ATC code(s)

D05A-X (Other antipsoriatics for topical use)

D11A-H (Agents for atopic dermatitis excluding corticosteroids)

EPhMRA code(s)

D5A (Topical Antipsoriasis Products)

D5X (Other Nonsteroidal Products for Inflammatory Skin Disorders)

Clinical trial(s)

Conditions	Phases	Interventions	Status
Dermatitis, Atopic	Phase 3	AN-2728	Active, not recruiting
Psoriasis	Phase 2	AN-2728	Completed
Plaque-Type Psoriasis	Phase 1	AN-2728	Completed

PAPER

Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis
Bioorg Med Chem Lett 2009, 19(8): 2129

http://www.sciencedirect.com/science/article/pii/S0960894X09002996

Tsutomu Akama ^,,

Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA

A series of phenoxy benzoxaboroles were synthesized and screened for their inhibitory activity against PDE4 and cytokine release. 5-(4-Cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2728) showed potent activity both in vitro and in vivo. This compound is now in clinical development for the topical treatment of psoriasis and being pursued for the topical treatment of atopic dermatitis

Scheme 1.

Reagents and conditions: (a) ethylene glycol, p-TsOH, toluene, reflux, 6 h (quant.); (b) K₂CO₃, DMF, 100 °C, overnight (82–96%); (c) 3 M HCl, THF, reflux, 2 h (80–100%); (d) NaBH₄, MeOH, rt, 1 h (quant.); (e) 3,4-dihydro-2H-pyran, camphorsulfonic acid, CH₂Cl₂, rt, 2 h (quant.); (f) (i-PrO)₃B, n-BuLi, THF, −78 °C to rt, 3 h; (g) 6 M HCl, THF, rt, 3 h (37–44%); (h) 6 M NaOH, MeOH, 1,4-dioxane, reflux, 6 days (79%); (i) diethylamine (for 5f) or morpholine (for 5g), EDCI, HOBt, DMAP, DMF, rt, overnight (41–70%).

PATENT

http://www.google.co.in/patents/WO2006089067A2?cl=en

4.2. q 5-(4-Cyanophenoxy)-l, 3-dihydro-l-hydroxy-2, 1-benzoxaborole (C17) [0264] ¹H-NMR (300 MHz,

δ ppm 4.95 (s, 2H), 7.08 (dd, J= 7.9, 2.1 Hz, IH), 7.14 (d, J= 8.8 Hz, IH), 7.15 (d, J= 2.1 Hz, IH), 7.78 (d, J= 7.9 Hz, IH), 7.85 (d, J= 9.1 Hz, 2H), 9.22 (s, IH).

PATENT

EXAMPLE 15

http://www.google.com/patents/WO2007095638A2?cl=en

4-(4-Cvanophenoxy)phenylboronic acid (C97)

(a) (4-cyanophenyl) (4-bromophenyl) ether. Under nitrogen, the mixture of 4-fluorobenzonitrile (7.35 g, 60.68 mmol), 4-bromophenol (10 g, 57.8 mmol) and potassium carbonate (12 g, 1.5 eq) in DMF (100 mL) was stirred at 100⁰C for 16 h and then filtered. After rotary evaporation, the residue was dissolved in ethyl acetate and washed with IN NaOH solution to remove unreacted phenol. The organic solution was dried and passed through a short silica gel column to remove the color and minor phenol impurity. Evaporation of the solution gave (4-cyanophenyl)(4- bromophenyl)ether (13.82 g, yield 87.2%) as a white solid. ¹H NMR (300 MHz, DMSO-de): δ 7.83 (d, 2H), 7.63 (d, 2H), 7.13 (d, 2H) and 7.10 (d, 2H) ppm.

(b) 4-(4-cyanophenoxy)phenylboronic acid. The procedure described in Example 2d was used for the synthesis of 4-(4-cyanophenoxy)phenylboronic acid using (4-cyanophenyl)(4-bromophenyl)ether as starting material. The title compound was obtained as a white solid. M.p.l94-198°C. MS: m/z = 239 (M+), 240 (M+ 1) (ESI+) and m/z = 238 (M-I) (ESI-). HPLC: 95.3% purity at 254 nm and 92.1% at 220 nm. ¹H NMR (300 MHz, DMSO-d₆ + D₂O): δ 7.83-7.76 (m, 4H), 7.07 (d, 2H) and 7.04 (d, 2H) ppm.

FURTHER METHOD

2-Bromo-5-(4-cvanophenoxy)benzyl Alcohol

¹H-NMR (300 MHz, CDCl₃) δ (ppm) 2.00 (br s, IH), 4.75 (s, 2H), 6.88 (dd, J= 8.5, 2.9 Hz, IH), 7.02 (d, J= 8.8 Hz, IH), 7.26 (d, J= 2.6 Hz, IH), 7.56 (d, J = 8.5 Hz, IH), 7.62 (d, J= 8.8 Hz, 2H).

PATENT

http://www.google.im/patents/EP1976536A2?cl=en

2.2.a 2-Bromo-5-(4-cyanophenoxy)benzyl Alcohol

¹H-NMR (300 MHz, CDCl₃) δ (ppm) 2.00 (br s, IH), 4.75 (s, 2H), 6.88 (dd, J= 8.5, 2.9 Hz, IH), 7.02 (d, J= 8.8 Hz, IH), 7.26 (d, J- 2.6 Hz, IH), 7.56 (d, J = 8.5 Hz, IH), 7.62 (d, J= 8.8 Hz, 2H).

2.2.b 2-Bromo-4-(4-cyanophenoxγ)benzyl Alcohol

¹H NMR (300 MHz, DMSO-d₆): δ 7.83 (d, 2H), 7.58 (d, IH), 7.39 (d, IH), 7.18 (dd, IH), 7.11- (d, 2H), 5.48 (t, IH) and 4.50 (d, 2H) ppm.

2.2.c 5- (4-Cyanophenoxy) -1 -Indanol

M.p.50-53°C. MS (ESI+): m/z = 252 (M+l). HPLC: 99.7% purity at 254 nm and 99.0% at 220 nm. ¹H NMR (300 MHz, DMSOd₆): δ 7.80 (d, 2H), 7.37 (d, IH), 7.04 (d, 2H), 6.98-6.93 (m, 2H), 5.27 (d, IH)₅ 5.03 (q, IH), 2.95-2.85 (m, IH), 2.75-2.64 (m, IH), 2.39-2.29 (m, IH) and 1.85-1.74 (m, IH) ppm.

2.2. d 2-Bromo-5-(tert-butyldimethylsiloxy)benzyl Alcohol [0429] ¹H-NMR (300 MHz, CDCl₃) δ (ppm) 0.20 (s, 6H), 0.98 (s, 9H), 4.67 (br s,lH), 6.65 (dd, J= 8.2, 2.6 Hz, IH), 6.98 (d, J= 2.9 Hz, IH), 7.36 (d, J= 8.8 Hz, IH).

3.2.k 2-Bromo-5-(2-cyanophenoχy)-l-(methoxymethoxymethyl)benzene [0443] ¹H-NMR (300 MHz, CDCl₃) δ (ppm) 3.41 (s, 3H), 4.64 (s, 2H), 4.76 (s, 2H), 6.8-6.9 (m, 2H), 7.16 (td, J= 7.6, 0.9 Hz, IH), 7.28 (d, J= 2.9 Hz, IH), 7.49 (ddd, J= 8.8, 7.6, 1.8 Hz, IH)₅ 7.56 (d, J= 8.5 Hz, IH), 7.67 (dd, J= 7.9, 1.8 Hz, IH).

EXAMPLE 32

Alternative Preparation of C17 -Intermediate

The procedure described in Example II I was followed for ¹H NMR characterization of the current alcohol-borate intermediate. ¹H NMR determination indicated there were 72.7 mol% of the desired alcohol-borate intermediate [2-bromo- 5-(4-cyanophenoxy)benzyl] diisopropyl borate, 20.7 mol% of an unknown intermediate and 6.5 mol% of unreacted alcohol. ¹H NMR (CDCl₃, 300 MHz) of [2- bromo-5-(4-cyanophenoxy)benzyl] diisopropyl borate: δ= 7.61 (d, J= 9.0 Hz, 2H), 7.52 (d, J= 8.4 Hz, IH), 7.15 (d, J= 3.0 Hz, IH), 7.03 (d, J= 8.7 Hz, 2H), 6.84 (dd, J= 8.7 Hz, J= 3.0 Hz, IH), 4.85 (s, 2H), 4.35 (septet, J= 6.1 Hz, 2H), 1.11 (d, J= 6.1 Hz, 12H) ppm.

PATENT

http://www.google.com/patents/US20090291917

(a) (4-cyanophenyl)(4-bromophenyl)ether. Under nitrogen, the mixture of 4-fluorobenzonitrile (7.35 g, 60.68 mmol), 4-bromophenol (10 g, 57.8 mmol) and potassium carbonate (12 g, 1.5 eq) in DMF (100 mL) was stirred at 100° C. for 16 h and then filtered. After rotary evaporation, the residue was dissolved in ethyl acetate and washed with 1N NaOH solution to remove unreacted phenol. The organic solution was dried and passed through a short silica gel column to remove the color and minor phenol impurity. Evaporation of the solution gave (4-cyanophenyl)(4-bromophenyl)ether (13.82 g, yield 87.2%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 7.83 (d, 2H), 7.63 (d, 2H), 7.13 (d, 2H) and 7.10 (d, 2H) ppm.
(b) 4-(4-cyanophenoxy)phenylboronic acid. The procedure described in Example 2d was used for the synthesis of 4-(4-cyanophenoxy)phenylboronic acid using (4-cyanophenyl)(4-bromophenyl)ether as starting material. The title compound was obtained as a white solid. M.p. 194-198° C. MS: m/z=239 (M+), 240 (M+1) (ESI+) and m/z=238 (M−1) (ESI−). HPLC: 95.3% purity at 254 nm and 92.1% at 220 nm. ¹H NMR (300 MHz, DMSO-d₆+D₂O): δ 7.83-7.76 (m, 4H), 7.07 (d, 2H) and 7.04 (d, 2H) ppm.

see

http://www.google.co.in/patents/WO2006089067A2?cl=en

see

http://www.google.com/patents/US20090291917

US5688928 *	Jun 7, 1995	Nov 18, 1997	Prolinx, Inc.	Phenylboronic acid complexing reagents derived from aminosalicylic acid
US5880188 *	May 26, 1995	Mar 9, 1999	Zeneca Limited	Oxaboroles and salts thereof, and their use as biocides
US5962498 *	Dec 2, 1994	Oct 5, 1999	Procyon Pharmaceuticals, Inc.	Protein kinase C modulators. C. indolactam structural-types with anti-inflammatory activity
US6369098 *	Oct 4, 2000	Apr 9, 2002	Bethesda Pharmaceuticals, Inc.	Dithiolane derivatives
US20030032673 *	Jul 19, 2002	Feb 13, 2003	Isis Innovation Limited	Therapeutic strategies for prevention and treatment of alzheimer’s disease
US20050239170 *	Jul 16, 2001	Oct 27, 2005	Hedley Mary L	Alpha-MSH related compounds and methods of use
US20060009386 *	May 12, 2005	Jan 12, 2006	The Brigham And Women’s Hospital, Inc.	Use of gelsolin to treat infections

Boron-containing small molecules as anti-inflammatory agents

US Pat. US8501712

Methods of treating anti-inflammatory conditions through the use of boron- containing small molecules are disclosed.

Boron-containing small molecules

US Pat. US8461336

… Francisco, CA Mar. 6-10, 2009. 6, “AN2728 … Francisco, CA Mar. 6-10, 2009. 7 , “AN2728 … Kyoto, Japan, May 14-18, 2008. 10, “AN2728 …

Compounds and Methods for Treating Pain

US Pat. US20130252924

AN2728, 5-(4-cyanophenoxy)-2,3- dihydro-1-hydroxy-2,1- …. UK-500,001, AN2728, DE-103, Tofisopam, Dextofisopam, Levotofisopam (USAN).

Boron-containing small molecules

US Pat. US8440642

… Dermatology Annual Meeting, San Francisco, CA Mar. 6-10, 2009. 6, “AN2728 … 7, “AN2728 … Francisco, CA May 6-10, 2009. 10, “AN2728 …

Phenylethylpyridine derivatives as pde4-inhibitors

US Pat. WO2014086855A1

… from the group consisting of AN-2728, AN-2898, CBS- 3595, apremilast, ELB- 353, KF-66490, K-34, LAS-37779, IBFB-211913, AWD-12-281, …

A method of inhibiting the expression of il-22 in activated t-cells

US Pat. WO2014083099A1

“AN2728” is the compound 4-(l-hydroxy-l,3-dihydro-2 … GSK256066, oglemilast, tetomilast, apremilast, AN2728, Compound A, Compound B, …

FMO3 inhibitors for treating pain

US Pat. EP2674161A1

AN2728, 5-(4-cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1- …. UK-500,001, AN2728, DE-103, Tofisopam, Dextofisopam, Levotofisopam (USAN).

Compounds and methods for treating pain

US Pat. CN103415286A

85.用于治疗疼痛的UK-500，001。 85. for the treatment of pain UK-500,001. 86.用于治疗疼痛的AN2728。 86. for the treatment of pain AN2728.

see full series on boroles

http://apisynthesisint.blogspot.in/p/borole-compds.html

do not miss out

///////////crisaborole, AN 2728, PHASE 3, Anti-inflammatory, Phosphodiesterase, Oxaborole, Psoriasis, Atopic dermatitis, borole

Novartis obtains European approval for Cosentyx to treat psoriasis

January 21, 2015 3:24 am / 3 Comments on Novartis obtains European approval for Cosentyx to treat psoriasis

Novartis obtains European approval for Cosentyx to treat psoriasis
Swiss drug-maker Novartis has received approval from the European Commission (EC) for its Cosentyx (secukinumab, formerly known as AIN457) to treat moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy.SEE

http://www.pharmaceutical-technology.com/news/newsnovartis-obtains-european-approval-for-cosentyx-to-treat-psoriasis-4492415?WT.mc_id=DN_News

PSORIAIS

secukinumab

Secukinumab is a human monoclonal antibody designed for the treatments of uveitis, rheumatoid arthritis, ankylosing spondylitis, and psoriasis. It targets member A from the cytokine family of interleukin 17.^[1]^[2] At present, Novartis Pharma AG, the drug’s developer, plans to market it under the trade name “Cosentyx.” ^[3] It is highly specific to the human immunoglobulin G1k (IgG1k) subclass.^[2]

In July 2014 secukinumab established superiority to placebo and to etanercept for the treatment of chronic plaque psoriasis in Phase III clinical trials.^[4] In October 2014, the FDA Dermatologic and Ophthalmic Drugs Advisory Committee unanimously voted to recommend the drug for FDA approval, although this vote in and of itself does not constitute an approval. However, the FDA typically follows recommendations from these committees.^[5] In October 2014, Novartis announced that the drug had achieved a primary clinical endpoint in two phase III clinical trials for ankylosing spondylitis.^[6] As of 28 October, the relevant FDA committee had not yet responded to these results. In early November 2014, Novartis also released the results of a Phase 3 study on Psoriatic Arthritis that yielded very promising results.^[7]

Although the drug was originally intended to treat rheumatoid arthritis, phase II clinical trials for this condition yielded disappointing results.^[8] Similarly, while patients in a phase II clinical trial for [psoriatic arthritis] did show improvement over placebo, the improvement did not meet adequate endpoints and Novartis is considering whether to do more research for this condition.^[9] Novartis has said that it is targeting approval and release in early 2015 for plaque psoriasis and ankyloding spondylitis indications.

It is also in a phase II clinical trial for Multiple Sclerosis ^[10] as it has exhibited efficacy in treating experimental autoimmune encephalomyelitis (EAE), an animal model of MS.

CAS registry numbers

875356-43-7 (heavy chain)
875356-44-8 (light chain)

References

“Statement On A Nonproprietary Name Adopted By The USAN Council: Secukinumab”. American Medical Association.
Hueber, W.; Patel, D. D.; Dryja, T.; Wright, A. M.; Koroleva, I.; Bruin, G.; Antoni, C.; Draelos, Z.; Gold, M. H.; Psoriasis Study, P.; Durez, P. P.; Tak, J. J.; Gomez-Reino, C. S.; Rheumatoid Arthritis Study, R. Y.; Foster, C. M.; Kim, N. S.; Samson, D. S.; Falk, D.; Chu, Q. D.; Callanan, K.; Nguyen, A.; Uveitis Study, F.; Rose, K.; Haider, A.; Di Padova, F. (2010). “Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis”. Science Translational Medicine 2 (52): 52ra72.doi:10.1126/scitranslmed.3001107. PMID 20926833. edit
http://www.medscape.com/viewarticle/835331
Langley RG, Elewski BE, Mark Lebwohl M, et al., for the ERASURE and FIXTURE Study Groups (July 24, 2014). “Secukinumab in Plaque Psoriasis — Results of Two Phase 3 Trials”. N Engl J Med 371: 326–338. doi:10.1056/NEJMoa1314258.
committees.http://www.familypracticenews.com/index.php?id=2934&type=98&tx_ttnews=306073^{[dead link]}
http://inpublic.globenewswire.com/2014/10/23/Novartis+AIN457+secukinumab+meets+primary+endpoint+in+two+Phase+III+studies+in+ankylosing+spondylitis+a+debilitating+joint+condition+of+the+spine+HUG1864939.html
http://www.medpagetoday.com/MeetingCoverage/ACR/48743
http://www.medscape.com/viewarticle/806510_6
http://www.ncbi.nlm.nih.gov/pubmed/23361084
http://clinicaltrials.gov/show/NCT01874340

Secukinumab
Monoclonal antibody
Type	Whole antibody
Source	Human
Target	IL17A
Clinical data
Legal status	Investigational
Identifiers
CAS number
ATC code	L04AC10
DrugBank	DB09029
Synonyms	AIN457
Chemical data
Formula	C₆₅₈₄H₁₀₁₃₄N₁₇₅₄O₂₀₄₂S₄₄
Molecular mass	147.94 kDa

XenoPort begins phase II trial of XP-23829 in patients with psoriasis

June 27, 2014 6:06 am / 1 Comment on XenoPort begins phase II trial of XP-23829 in patients with psoriasis

XP 23829 from Xenoport is an interesting molecule and as on 27 July 2014, I did not find conclusive evidence

See some structures below

Not sure about the structure of XP 23829

Best fit

Not sure?

(N,N-dimethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

I AM NOT SURE ABOUT THIS ONE ALSO????????

As Football worldcup2014 goes on in Brazil

A thought for it is due…………

……………………………………………………

Best fit is probably is as shown below, and there are reasons

(N,N- Diethylcarbamoyl)methyl methyl (2E)but-2-ene-l,4-dioate

Introduction

(N,N-Diethylcarbamoyl)methyl methyl (2E)-but-2-ene-1,4-dioate

As per patent……..http://www.google.com/patents/WO2014031844A1?cl=en Links

C₁₁ H₁₇ N O_{5, mw 243.13}

M.p.: 53-56 °C.

¹ H NMR (CDCI₃, 400 MHz): δ 6.99-6.90 (m, 2H), 4.83 (s, 2H), 3.80 (s, 3H), 3.39 (q, J = 1.1 Hz, 2H), 3.26 (q, J = 7.2 Hz, 2H), 1 .24 (t, J = 7.2 Hz, 3H), 1 .14 (t, J = 7.2 Hz, 3H). MS (ESI): m/z 244.13 (M+H)⁺.

Cas…….1208229-58-6

XP-23829 PROBABLE

For the treatment of moderate-to-severe chronic plaque-type psoriasis.

XP-H-093

US8148414 Links Basic patent

Xenoport, Inc. Innovator

XenoPort has initiated a phase II trial of XP-23829, a proprietary investigational next-generation fumaric acid product candidate (ClinicalTrials.gov Identifier NCT02173301). The multicenter, randomized, double-blind, placebo-controlled study is designed to assess the efficacy and safety of XP-23829 as a potential treatment of patients with moderate to severe chronic plaque-type psoriasis. XenoPort expects to enroll approximately 200 subjects in this trial, which is being conducted in the U.S. The study will include a screening and washout phase of up to 4 weeks, a 12-week treatment phase and a 4-week post-treatment phase. Eligible study subjects will be randomized to placebo or one of three treatment arms of XP-23829: 400 or 800 mg once daily or 400 mg twice daily. The primary endpoint will examine the percent change in Psoriasis Area and Severity Index (PASI) score from baseline at the end of week 12. Secondary endpoints will include the proportion of subjects who achieve a reduction of 75% or greater from baseline in PASI (PASI75) score and subjects who achieve a Static Physicians Global Assessment score of “clear” or “almost clear.” Topline results are expected in the third quarter of 2015 (XenoPort News Release).

XP23829 — A Prodrug of Monomethyl Fumarate

Our third product candidate, XP23829, is in Phase 1 clinical development. Provided we are able to demonstrate the safety and desired pharmacokinetic, or PK, profile of XP23829 in our Phase 1 trials, we believe that XP23829 could be a potential treatment of patients with RRMS, psoriasis and/or certain other disorders where the mechanism of action of XP23829 may be relevant. For example, we are exploring the potential of XP23829 to protect against neurodegeneration in experimental preclinical models of Parkinson’s disease through a grant from The Michael J. Fox Foundation. We hold a composition-of-matter patent and a formulation patent in the United States on XP23829 and hold patents or pending patent applications directed to the XP23829 methods of synthesis and use in the United States. We have also filed applications directed to the XP23829 composition of matter and methods of synthesis and use in other jurisdictions.

Prodrug Background

XP23829 is a fumaric acid ester compound and a patented prodrug of MMF. Fumaric acid ester compounds have shown immuno-modulatory and neuroprotective effects in cell-based systems and preclinical models of disease. A product containing a combination of fumaric acid ester compounds, known as Fumaderm, is approved in Germany for the treatment of psoriasis. Tecfidera (a formulation of DMF, also known as BG-12) from Biogen Idec Inc. is another fumaric acid ester prodrug that converts to MMF in the body. Phase 3 clinical trials of Tecfidera as a potential treatment for RRMS showed statistically significant benefits of Tecfidera versus placebo. Tecfidera is currently under U.S. regulatory review as a potential treatment for RRMS.

Our Prodrug

XP23829 is a novel prodrug of MMF that we believe may provide improved tolerability and efficacy compared to DMF. In preclinical studies that compared molar equivalent doses of XP23829 to DMF, XP23829 provided higher blood levels of the biologically active molecule MMF and a similar or greater degree of efficacy in MS and psoriasis animal models. Toxicology studies conducted in two species showed that XP23829 caused less stomach irritation when compared to DMF.

Phase 1 Clinical Trial in Healthy Volunteers

In October 2012, we reported favorable preliminary results from our first Phase 1 clinical trial in healthy adults designed to assess the pharmacokinetics, safety and tolerability of single doses of four different formulations of XP23829. The trial was a randomized, double-blind, two-period crossover, food effect comparison clinical trial of XP23829. Sixty subjects were assigned to five cohorts of 12, with each cohort receiving one of four different formulations of XP23829 or placebo. The trial demonstrated that administration of XP23829 resulted in the expected levels of MMF in the blood. As anticipated, the four formulations produced

April 4, 2012

http://investor.xenoport.com/releasedetail.cfm?ReleaseID=708145 Links
XenoPort Awarded U.S. Patent Directed to Composition and Formulations of XP23829, a Novel Fumarate Analog for the Potential Treatment of Relapsing-Remitting Multiple Sclerosis and Psoriasis
SANTA CLARA, Calif.–(BUSINESS WIRE)–Apr. 4, 2012– XenoPort, Inc. (Nasdaq: XNPT) announced today that it was awarded U.S. Patent 8,148,414 for “Prodrugs of Methyl Hydrogen Fumarate, Pharmaceutical Compositions Thereof, and Methods of Use.” The term of the patent extends until 2029, subject to potential Hatch-Waxman patent term extensions.

The patent is directed to the XP23829 compound, analogs thereof and formulations thereof. A related U.S. patent application directed to therapeutic uses of XP23829 is now pending.

XP23829 is a prodrug of methyl hydrogen fumarate, also known as monomethyl fumarate (MMF). In cell- and animal-based models, MMF has been shown to exhibit immuno-modulatory properties and inhibit damage from oxidative stress.

In XenoPort’s preclinical animal studies that compared molar equivalent doses of XP23829 to dimethyl fumarate (DMF), another prodrug of MMF, XP23829 demonstrated a greater degree of efficacy in animal models of both multiple sclerosis (MS) and psoriasis. Toxicology studies conducted in two species showed that XP23829 caused less stomach irritation compared to DMF.

XenoPort intends to file an Investigational New Drug Application (IND) for XP23829 for the treatment of relapsing remitting MS with the U.S. Food and Drug Administration (FDA) in the second quarter of 2012 and expects to initiate human clinical trials later this year.

XenoPort owns all rights to XP23829.

About XenoPort

XenoPort is a biopharmaceutical company focused on developing and commercializing a portfolio of internally discovered product candidates for the potential treatment of neurological disorders. Horizant® (gabapentin enacarbil) Extended-Release Tablets is XenoPort’s first FDA-approved product. GlaxoSmithKline holds commercialization rights and certain development rights for Horizant in the United States. Regnite® (gabapentin enacarbil) is approved for the treatment of moderate-to-severe primary restless legs syndrome in Japan. Astellas Pharma Inc. holds all development and commercialization rights for Regnite in Japan and five Asian countries. XenoPort holds all other world-wide rights and has co-promotion and certain development rights to gabapentin enacarbil in the United States. XenoPort’s pipeline of product candidates includes potential treatments for patients with postherpetic neuralgia, spasticity and Parkinson’s disease.

To learn more about XenoPort, please visit the company Website at http://www.XenoPort.com.

More info about this drug

SEE a patent

WO 2010022177

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WO 2013181451

http://www.google.com/patents/WO2013181451A1?cl=en Links

Scheme 5:

ONE OUT OF THESE

Example 6: (/V,/V-Diethylcarbamoyl)methyl methyl (2£)but-2-ene-1 ,4-dioate

[0138] Following general procedure A, methyl hydrogen fumarate (MHF) (0.39 g, 3.00 mmol) dissolved in NMP was reacted at about 55 °C with 2-chloro-/V,/V-diethylacetamide (0.44 g, 3.00 mmol) in the presence of CsHC0₃ (0.69 g, 3.60 mmol) to afford 0.37 g (51 % yield) of the title compound after purification by silica gel column chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1 :1 ) as eluent. M.p.: 53-56 °C. ¹ H NMR (CDCI₃, 400 MHz): δ 6.99-6.90 (m, 2H), 4.83 (s, 2H), 3.80 (s, 3H), 3.39 (q, J = 1.1 Hz, 2H), 3.26 (q, J = 7.2 Hz, 2H), 1 .24 (t, J = 7.2 Hz, 3H), 1 .14 (t, J = 7.2 Hz, 3H). MS (ESI): m/z 244.13 (M+H)⁺.

Example 7: Methyl 2-morpholin-4-yl-2-oxoethyl (2 £)but-2-ene-1 ,4-dioate

[0139] Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at about 55 °C with 4-(chloroacetyl) morpholine (0.75 g, 4.61 mmol) in the presence of CsHC0₃ (0.89 g, 4.61 mmol) to afford 0.34 g (35% yield) of the title compound as a white solid after purification by mass-guided preparative HPLC and lyophilization. M.p.: 124 to 126°C; ¹ H NMR (CDCI₃, 400 MHz): δ 6.97-6.91 (m, 2H), 4.84 (s, 2H), 3.82 (s, 3H), 3.72-3.70 (m, 4H), 3.64-3.62 (m, 2H), 3.46-3.41 (m, 2H). MS (ESI): m/z 258.04 (M+H)⁺. Example 8: A/,A/-Dimethylcarbamoyl)methyl methyl (2E)but-2-ene-1 ,4-dioate

[0140] Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at about 55 °C with /V,/V-dimethyl chloroacetamide (0.56 g, 4.61 mmol) in the presence of CsHC0₃ (0.89 g, 4.61 mmol). The crude material was precipitated out from a mixture of ethyl acetate (EtOAc) and hexanes (Hxn) (1 :1 ) to provide a white solid. This solid was further dissolved in dichloromethane (DCM) and the organic layer washed with water. After removal of the solvents 0.55 g (67% yield) of the title compound was obtained as a white solid. ¹ H NMR (CDCI₃, 400 MHz): δ 6.98- 6.90 (m, 2H), 4.84 (s, 2H), 3.80 (s, 3H), 2.99-2.97 (2s, 6H). MS (ESI): m/z 216 (M+H)⁺.

Example 9: Methyl (2-morpholino-4-ylethyl) fumarate

[0141] Following general Procedure A, methyl hydrogen fumarate (MHF) dissolved in NMP is reacted at about 55 °C with 4-(chloroethyl) morpholine (0.75 g, 4.61 mmol) in the presence of CsHC0₃ to afford the title compound after purification by mass-guided preparative HPLC and lyophilization. Example 10: Methyl (3-mor holino-4-ylpropyl) fumarate

[0142] Following the procedure of Methyl (2-morpholino-4-ylethyl) fumarate, and replacing 4-(chloroethyl) morpholine with 4-(chloropropyl) morpholine provides the title compound.

Example 11 : Methyl (4-morpholino-4-ylbutyl) fumarate

[0143] Following the procedure of Methyl (2-morpholino-4-ylethyl) fumarate, and replacing 4-(chloroethyl) morpholine with 4-(chlorobutyl) morpholine provides the title compound. Example 12: Methyl 5-morpholino-4-ylpentyl) fumarate

[0144] Following the procedure of Methyl (2-morpholino-4-ylethyl) fumarate, and replacing 4-(chloroethyl) morpholine with 4-(chloropentyl) morpholine provides the title compound. Example 13: (A/-cyclopropyl-W-ethylcarbamoyl)methyl methyl 2(E)but-2-ene-1 ,4-dioate

[0145] Following the general procedure A, methyl hydrogen fumarate (MHF) (38.7 g, 0.297 mol) suspended in toluene (100 mL) was reacted at about 80 °C with 2-chloro-/V-cyclopropyl- N-ethylacetamide (48 g, 0.297 mol) in the presence of W,/V-diisopropylethylamine (DIEA; 42.3 g, 57 mL, 0.327 mol) to afford 50 g (63.3%) of the title compound after recrystallization using methyl ferf-butyl ether. The crystalline compound had a melting point of 92.1 °C. ¹ H NMR (CDCI₃, 400 MHz): δ 7.01 -6.92 (m, 2H), 4.99 (s, 2H), 3.81 (s, 3H), 3.44 (q, J = 7.2 Hz, 2H), 2.69-2.66 (m, 1 H), 1 .14 (t, J = 7.2 Hz, 3H), 0.94-0.91 (m, 2H), 0.83-0.81 (m, 2H). MS (ESI): m/z 256.2 (M+H)⁺.

Example 14: (/V-cyclopropyl-/V-methylcarbamoyl)methyl methyl 2(E)but-2-ene-1 , 4- dioate

[0146] Following general procedure A, methyl hydrogen fumarate (MHF) (38.7 g, 0.40 mol) suspended in toluene (100 mL) was reacted at about 80 °C with 2-chloro-/V-cyclopropyl-/V- methylacetamide (60 g, 0.40 mol) in the presence of Ν,Ν-diisopropylethylamine (DIEA; 57.8 g, 78 mL, 0.44 mol) to afford 50 g (50.86%) of the title compound after recrystallization using methyl fe/t-butyl ether. The crystalline compound had a melting point of 93.6 °C. ¹ H NMR (CDCI₃, 400 MHz): δ 7.01 -6.91 (m, 2H), 5.01 (s, 2H), 3.82 (s, 3H), 2.94 (s, 3H), 2.73-2.68 (m, 1 H), 0.94-0.86 (m, 2H), 0.83-0.78 (m, 2H). MS (ESI): m/z 242.2 (M+H)⁺.

Example 15: Methyl 2-oxo-2-pyrrolidinylethyl 2(E)but-2-ene-1 ,4-dioate

[0147] Following general procedure A, methyl hydrogen fumarate (MHF) (20.78 g, 0.159 mol) suspended in toluene (60 mL) was reacted at about 80 °C with 2-chloro-1 -pyrrolidin-1 -yl- ethanone (23.5 g, 0.159 mol) in the presence of N,N-diisopropylethylamine (DIEA; 22.69 g, 31 .5 mL, 0.175 mol) to afford 24 g (62.3%) of the title compound after recrystallization using methyl fe/t-butyl ether. The crystalline compound had a melting point of 102.1 °C. ¹ H NMR (CDCI₃, 400 MHz): δ 7.00-6.92 (m, 2H), 4.75 (s, 2H), 3.81 (s, 3H), 3.53-3.49 (t, J = 6.8 Hz, 2H), 3.42-3.39 (t, J = 6.8 Hz, 2H), 2.20-1 .97 (m, 2H), 1 .91 -1 .82 (m, 2H). MS (ESI): m/z 242 (M+H)⁺.

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Patent

http://www.google.co.in/patents/US8148414

(I):

Example 1(N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate (1)…………. best fit

Following general procedure A, methyl hydrogen fumarate (MHF) (0.39 g, 3.00 mmol) dissolved in NMP was reacted at ca. 55° C. with 2-chloro-N,N-diethylacetamide (0.44 g, 3.00 mmol) in the presence of CsHCO₃(0.69 g, 3.60 mmol) to afford 0.37 g (51% yield) of the title compound (1) after purification by silica gel column chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:1) as eluent. M.p.: 53-56° C. ¹H NMR (CDCl₃, 400 MHz): δ 6.99-6.90 (m, 2H), 4.83 (s, 2H), 3.80 (s, 3H), 3.39 (q, J=7.2 Hz, 2H), 3.26 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.14 (t, J=7.2 Hz, 3H). MS (ESI): m/z 244.13 (M+H)⁺.

Example 162-(4-Acetylpiperazinyl)-2oxoethyl methyl(2E)but-2ene-1,4-dioate (16)

Methyl 2-oxo-2-piperazinylethyl(2E)but-2-ene-1,4-dioate hydrochloride (14) (0.20 g, 0.68 mmol) was reacted with acetyl chloride (AcCl) (0.60 mL, 0.66 g, 0.84 mmol) and diisopropylethylamine (0.70 mL, 0.52 g, 4.0 mmol) in dichloromethane (DCM). Following aqueous work-up, the crude product was purified by silica gel flash chromatography to afford 0.12 g (54% yield) of the title compound (16) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 6.98-6.93 (m, 2H), 4.86 (s, 2H), 3.83 (s, 3H), 3.66 3.63 (m, 4H), 3.50-3.40 (m, 4H), 2.14 (s, 3H). MS (ESI): m/z 299.12 (M+H)⁺.

Example 9N,N-Dimethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate (9)

Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with N,N-dimethyl chloroacetamide (0.56 g, 4.61 mmol) in the presence of CsHCO₃(0.89 g, 4.61 mmol). The crude material was precipitated out from a mixture of ethyl acetate (EtOAc) and hexanes (Hxn) (1:1) to provide a white solid. This solid was further dissolved in dichloromethane (DCM) and the organic layer washed with water. After removal of the solvents 0.55 g (67% yield) of the title compound (9) was obtained as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 6.98-6.90 (m, 2H), 4.84 (s, 2H), 3.80 (s, 3H), 2.99-2.97 (2s, 6H). MS (ESI): m/z 216 (M+H)⁺.

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http://www.google.com/patents/WO2014031844A1?cl=en

Compound (1).

Table 1 : Flushing Incidence as a Function of MMF Cmax

*Formulation 2 is the dosage form described in Example 10; Formulation 3 is the dosage form described in Example 3 ; Formulation 4 is the dosage form described in Example 5 ;

** maximum average Concentration; ***average Cmax; Poster (see above); Compound (1) referred to in the above table is an MMF prodrug of Formula (II); (N,N- Diethylcarbamoyl)methyl methyl (2£)but-2-ene-l,4-dioate having the following chemical structure:

Compound (1).

The maximum slope values ( dose and ng) for different dosage treatments are given in Table 2. The Figures 15-16 show plots of maximum MMF slope vs flushing incidence. The curves in the figures were fitted using a Hill Em_ax model. Table 2

Compound, Flushing

Table 3: Composition of Enteric Coated Sustained Release Tablet (15% HPMC in Core)

Quantity Quantity

Component Manufacturer Role

(mg tablet) (%w/w)

Vertellus (Greensboro,

Triethyl Citrate Plasticizer 1.25 0.42

NC)

Emerson Resources Anti- tacking

PlasAC YL™ T20 2.41 0.80

(Norristown, PA) agent

Total Enteric

27.87 9.30 Coating

Total Tablet 334.69 111.68

[00191] The tablets were made according to the following steps. The core tablets were prepared using a wet granulation process. The granulation was performed in two batches at 456 g per batch. Compound (1) and hydroxypropyl cellulose were passed through a conical mill with a 610 micron round holed screen. Compound (1) and hydroxypropyl cellulose were then combined in a Key KG- 5 granulator bowl and mixed with water addition for approximately 7 minutes. The wet granules were dried in a Glatt GPCG-1 fluid bed dryer at 40 °C. The two portions of dried granules were sized by passing through a conical mill with an approximately 1300 micron grater type screen. The milled granules were blended with the hypromellose 2208, silicon dioxide, and lactose monohydrate for 10 minutes in an 8 quart (7.6 1) V-blender. This blend was passed through an 850 micron mesh screen. The magnesium stearate was passed through a 600 micron mesh screen and blended with the additional core materials in the V-blender for 5 minutes. Core tablets (299.69 mg) were compressed using a GlobePharma Minipress II rotary tablet press with 8.6 mm round concave tooling. The core tablets had a final mean hardness of approximately 12 kp. For the coating, an aqueous suspension was prepared by mixing with an impeller 63.8 g Opadry 03019184 with 770.7 g of purified water. The water contained in the suspension is removed during the film coating process and therefore not included in the final formulation in Table 3. The tablets were coated with the aqueous suspension in an O’ Hara Technologies Labcoat M coater with a 12″ (30.5 cm) diameter perforated pan until the desired weight gain of barrier coat was achieved. The coating process occurred at an inlet temperature of approximately 52 °C and an outlet temperature of 36 °C. After coating, the tablets were dried for 2 hours at 40 °C. An aqueous suspension was prepared by mixing with an impeller 405.1 g methacrylic acid copolymer dispersion, 6.3 g triethyl citrate, 60.6 g PlasACRYL™ T20 with 228.1 g water. The water contained in the methacrylic acid copolymer dispersion and the

PlasACRYL™ T20 is removed during the film coating process and therefore not included in the final formulation in Table 3. The tablets were coated with the aqueous suspension in the O’ Hara Technologies Labcoat M coater until the desired weight gain of enteric film was achieved. The coating process occurred at an inlet temperature of approximately 40 °C and an outlet temperature of 30 °C. After coating, the tablets were dried for 2 hours at 40 °C.

Example 2

In Vitro Dissolution Profile of Example 1 Dosage Form

[00192] A two-stage dissolution method was used to determine the in vitro dissolution profile of dosage forms prepared according to Example 1. The 2-stage dissolution test was used to better approximate the pH conditions experienced by a dosage form after swallowing by a patient, i.e., low pH of the stomach followed by near neutral pH of the intestines. The dosage forms were first placed into a dissolution vessel (USP, Type I, basket) containing 750 mL of 0.1 N hydrochloric acid (pH 1.2). After 2 hours, 250 mL of 200 mM tribasic sodium phosphate was added to the vessel resulting in a pH adjustment from 1.2 to 6.8. The dissolution medium was kept at 37 °C and was agitated at 100 rpm.

[00193] For the Example 1 dosage forms, samples of the dissolution medium were withdrawn after 1 and 2 hours in the low pH stage, and at 0.5, 2, 4, 7, 10, and 14 hours following buffer addition. The released amount of the MMF prodrug in the samples was determined by reverse phase HPLC using a C18 column and a 7 minute gradient method according to Table 4 where Mobile Phase A is water/0.1 ]¾Ρθ4 and Mobile Phase B is water/acetonitrile/H₃PC>4 (10/90/0.1 by volume) with UV detection at 210 nm.

Table 4: HPLC Gradient Conditions

[00194] As shown in FIG. 1, for dosage forms prepared according to Example 1, drug release is delayed for approximately 2 hours, followed by sustained release reaching >90 at 12 hours.

Example 3

Preparation of Delayed Sustained Release Dosage Form (Enteric Coated, 15% HPMC in Core, without Barrier Layer) [00195] Delayed sustained release tablets containing compound (1) were made having the ingredients shown in Table 5:

Table 5: Composition of Enteric Coated Sustained Release Tablet (15% HPMC in Core, without Barrier Layer)

[00196] The tablets were made according to the following steps. The core tablets were prepared using a wet granulation process. The granulation was performed in two batches at 463.9 g per batch. Compound (1) and hydroxypropyl cellulose were passed through a conical mill with a 610 micron round holed screen. Compound (1) and hydroxypropyl cellulose were then combined in a Key KG- 5 granulator bowl and mixed with water addition for approximately 10 minutes. The wet granules were dried in a Glatt GPCG-1 fluid bed dryer at 40 °C. The two portions of dried granules were blended with silicon dioxide and sized by passing through a conical mill with an approximately 1300 micron grater type screen. The milled granules were blended with the hypromellose 2208 and lactose monohydrate for 10 minutes in an 8 quart (7.6 1) V-blender. This blend was passed through an 850 micron mesh screen. The magnesium stearate was passed through a 600 micron mesh screen and blended with the additional core materials in the V-blender for 5 minutes. Core tablets (299.68 mg) were compressed using a GlobePharma Minipress II rotary tablet press with 11/32″ round concave tooling. The core tablets had a final mean hardness of approximately 11 kp. For the coating, an aqueous suspension was prepared by mixing with an impeller 578.7 g methacrylic acid copolymer dispersion, 9.0 g triethyl citrate, 86.5 g PlasACRYL™ T20 with 325.8 g water. The water contained in the methacrylic acid copolymer dispersion and the

PlasACRYL™ T20 is removed during the film coating process and therefore not included in the final formulation in Table 4. The tablets were coated with the aqueous suspension in the O’ Hara Technologies Labcoat M coater until the desired weight gain of enteric film was achieved. The coating process occurred at an inlet temperature of approximately 41 °C and an outlet temperature of 31 °C. After coating, the tablets were dried for 2 hours at 40 °C.

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WO 2014071371

http://www.google.com/patents/WO2014071371A1?cl=en

(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1 ,4-dioate has the following chemical structure:

This compound was synthesized in Example 1 of Gangakhedkar et al., U.S. Patent No. 8,148,414. The compound is a prodrug of methyl hydrogen fumarate (MHF) and has a disclosed melting point of between 53 °C and 56 °C.

Cocrystals are crystals that contain two or more non-identical molecules that form a crystalline structure. The intermolecular interactions between the non-identical molecules in the resulting crystal structures can result in physical and chemical properties that differ from the properties of the individual components. Such properties can include, for example, melting point, solubility, chemical stability, mechanical properties and others. Examples of cocrystals may be found in the Cambridge Structural Database and in Etter, et al.,

“The use of cocrystallization as a method of studying hydrogen bond preferences of 2-aminopyridine” J. Chem. Soc, Chem. Commun. (1990), 589-591 ; Etter, et al., “Graph-set analysis of hydrogen-bond patterns in organic crystals” Acta Crystallogr., Sect. B, Struct. Sci. (1990), B46: 256-262; and Etter, et al., “Hydrogen bond directed cocrystallization and molecular recognition properties of diarylureas” J. Am. Chem. Soc. (1990), 1 12: 8415-8426. Additional information relating to cocrystals can be found in: Carl Henrik Gorbotz and Hans-Petter Hersleth,

“On the inclusion of solvent molecules in the crystal structures of organic compounds”; Acta Cryst. (2000), B56: 625-534; and Senthil Kumar, et al., “Molecular Complexes of Some Mono- and Dicarboxylic Acids with trans-1 ,4,-Dithiane-1 ,4-dioxide” American Chemical Society, Crystal Growth & Design (2002) , 2(4) : 313-318.

(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1 ,4-dioate is a prodrug of methyl hydrogen fumarate. Once administered, the compound is metabolized in vivo into an active metabolite, namely, methyl hydrogen fumarate (MHF) which is also referred to herein as monomethyl fumarate (MMF). The in vivo metabolism of (N,N-Diethylcarbamoyl)methyl

(N,N-Diethylcarbamoyl)methyl methyl Methyl hydrogen fumarate N ^ diethyl glycolamide

(2E)but-2-ene-1 ,4-dioate

Table 1

As can be seen from the data in Table 1 , the six cocrystals disclosed herein each exhibit a higher melting point than crystalline (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1 ,4- dioate.

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Steady state pharmacokinetics of formulations of XP23829, a novel prodrug of monomethyl fumarate (MMF), in healthy subjects
66th Annu Meet Am Acad Neurol (AAN) (April 26-May 3, Philadelphia) 2014, Abst P1.188

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Lymphocyte and eosinophil responses in healthy subjects dosed with Tecfidera and XP23829, a novel fumaric acid ester (FAE)
66th Annu Meet Am Acad Neurol (AAN) (April 26-May 3, Philadelphia) 2014, Abst P1.201

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A comparison of XP23829 with DMF, the active ingredient of BG-12
4th Cooperative Meet Consorti Mult Scler Cent (CMSC) Am Comm Treat Res Mult Scler (ACTRIMS) (May 30-June 2, San Diego) 2012, Abst SC03

http://annualmeeting.mscare.org/index.php?option=com_content&view=article&id=174&Itemid=101

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Favorable metabolism and pharmacokinetics of formulations of XP23829, a novel fumaric acid ester, in healthy subjects
65th Annu Meet Am Acad Neurol (AAN) (March 16-23, San Diego) 2013, Abst P05.189

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Comparison of the efficacy and tolerability of a novel methyl hydrogenfumarate prodrug with dimethyl fumarate in rodent EAE and GI irritation models
Neurology 2011, 76(9): Abst P05.040

WO2013119791A1 *	Feb 7, 2013	Aug 15, 2013	Xenoport, Inc.	Morpholinoalkyl fumarate compounds, pharmaceutical compositions, and methods of use
US20120034303 *	Jan 8, 2010	Feb 9, 2012	Forward Pharma A/S	Pharmaceutical formulation comprising one or more fumaric acid esters in an erosion matrix
US20120095003 *	Oct 14, 2011	Apr 19, 2012	Xenoport, Inc.	Methods of using prodrugs of methyl hydrogen fumarate and pharmaceutical compositions thereof
US20120157523 *	Oct 14, 2011	Jun 21, 2012	Xenoport, Inc.	Prodrugs of methyl hydrogen fumarate, pharmaceutical compositions thereof, and methods of use

	K Gogas ET AL: “Comparison of the efficacy and tolerability of a novel methylhydrogenfumarate prodrug with dimethylfumarate in rodent experimental autoimmune encephalomyelitis and GI irritation models“, 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) & 15th Annual Conference of Rehabilitation in MS (RIMS), 15 October 2010 (2010-10-15), XP055076728, Retrieved from the Internet: URL:http://registration.akm.ch/einsicht.php?XNABSTRACT_ID=115706&XNSPRACHE_ID=2&XNKONGRESS_ID=126&XNMASKEN_ID=900 [retrieved on 2013-08-27]

WO2013119791A1 *	Feb 7, 2013	Aug 15, 2013	Xenoport, Inc.	Morpholinoalkyl fumarate compounds, pharmaceutical compositions, and methods of use
US20100048651 *	Aug 19, 2009	Feb 25, 2010	Xenoport, Inc.	Prodrugs of methyl hydrogen fumarate, pharmaceutical compositions thereof, and methods of use

US8669281	20 Sep 2013	11 Mar 2014	Alkermes Pharma Ireland Limited	Prodrugs of fumarates and their use in treating various diseases
WO2014031894A1	22 Aug 2013	27 Feb 2014	Xenoport, Inc.	Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
WO2014071371A1	5 Nov 2013	8 May 2014	Xenoport, Inc.	Cocrystals of (n,n-diethylcarbamoyl)methyl methyl (2e)but-2-ene-1,4-dioate

Amgen-AstraZeneca Psoriasis Drug Brodalumab (AMG 827) Hits Phase 3 Endpoints

May 13, 2014 3:32 am / 1 Comment on Amgen-AstraZeneca Psoriasis Drug Brodalumab (AMG 827) Hits Phase 3 Endpoints

AstraZeneca and Amgen announced that the Phase 3 AMAGINE-1TM study evaluating brodalumab in patients with moderate-to-severe plaque psoriasis met all primary and secondary endpoints for both evaluated doses.

Brodalumab is a human monoclonal antibody designed for the treatment of inflammatory diseases.^[1] It is being tested for the treatment of moderate to severe psoriasis^[2] in Phase III clinical trials as of November 2013.^[3]^[4]

Brodalumab was developed by Amgen, Inc.

Mechanism of action

Brodalumab binds to the interleukin-17 receptor and so prevents interleukin 17 (IL-17) from activating the receptor. This mechanism is similar to that of another anti-psoriasis antibody, ixekizumab, which however binds to IL-17 itself.^[2]
At present, brodalumab is the only experimental drug in development that inhibits the IL-17 receptor, thus inhibiting several of the IL-17 ligands at once from transmitting signals to the body. Other agents currently in development seek to target the individual IL-17 ligands. By inhibiting the attachment of these ligands with the receptor, brodalumab stops the body from receiving signals that may otherwise cause inflammation and other ailments.

Researchers are currently investigating brodalumab for the treatment of psoriasis (Phase II and planned Phase III), asthma (Phase II), and psoriatic arthritis (Phase II).

Psoriasis is a chronic disease of the immune system that causes the skin cells to grow at a faster rate. Worldwide, the condition affects around 125 million individuals. Even though several types of psoriasis exist, around 80% of sufferers have plaque psoriasis. Plaque psoriasis can cause painful and itchy red, scaly patches to appear on the skin.

Brodalumab

(AMG 827)
Monoclonal antibody
Type	Whole antibody
Source	Human
Target	Interleukin 17 receptor A
Clinical data
Legal status	Investigational
Identifiers
CAS number	1174395-19-7
ATC code	None
KEGG	D10061
Chemical data
Formula	C₆₃₇₂H₉₈₄₀N₁₇₁₂O₁₉₈₈S₅₂
Mol. mass	144.06 kDa

About Brodalumab (AMG 827)

Brodalumab is a novel human monoclonal antibody that binds to the interleukin-17 (IL-17) receptor and inhibits inflammatory signaling by blocking the binding of several IL-17 ligands to the receptor. By stopping IL-17 ligands from activating the receptor, brodalumab prevents the body from receiving signals that may lead to inflammation. The IL-17 pathway plays a central role in inducing and promoting inflammatory disease processes. In addition to moderate-to-severe plaque psoriasis (Phase 3), brodalumab is currently being investigated for the treatment of psoriatic arthritis (Phase 3) and asthma (Phase 2).

About the Amgen and AstraZeneca Collaboration

In April 2012, Amgen and AstraZeneca formed a collaboration to jointly develop and commercialize five monoclonal antibodies from Amgen’s clinical inflammation portfolio. With oversight from joint governing bodies, Amgen leads clinical development and commercialization for brodalumab (Phase 3 for moderate-to-severe plaque psoriasis and psoriatic arthritis, Phase 2 for asthma) and AMG 557/MEDI5872 (Phase 1b for autoimmune diseases such as systemic lupus erythematosus). AstraZeneca, through its biologics arm MedImmune, leads clinical development and commercialization for MEDI7183/AMG 181 (Phase 2 for ulcerative colitis and Crohn’s disease), MEDI2070/AMG 139 (Phase 2 for Crohn’s disease) and MEDI9929/AMG 157 (Phase 2 for asthma).

About Amgen

Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgen focuses on areas of high unmet medical need and leverages its biologics manufacturing expertise to strive for solutions that improve health outcomes and dramatically improve people’s lives. A biotechnology pioneer since 1980, Amgen has grown to be the world’s largest independent biotechnology company, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.

For more information, visit www.amgen.com and follow us on www.twitter.com/amgen.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com.

References

http://ksclinic.exblog.jp/18270693/

学術面で最初の講演は、米国のJames Krueger教授による「Th1細胞,Th17細胞,Th22細胞が複雑なサイトカインネットワークによって、細胞レベル、分子レベルで乾癬を引き起こす」でした。その要約を示すスライドを幾枚か失敬します（Krueger先生、ごめんなさい）。

乾癬の原因究明、病態（病気の起こり方）解明の主役となった免疫学的研究の最先端を行くKrueger先生の、最新情報がコンパクトにまとまった素晴らしい講演でした。生物学的製剤の治療根拠となるサイトカインネットワークは、現在TipDC – Th17経路によって、きわめて明快に説明されるようになり、Th17細胞が放出するIL17が表皮細胞（ケラチノサイト）の乾癬化を起こします。現在使用されている抗TNFα製剤、抗IL12/23製剤が、より上流（免疫反応の根っこ）で免疫反応を抑制するのに比べ、IL17はより末梢における乾癬の原因サイトカインであることから、IL17の抑制は、より乾癬をピンポイントで、そして副作用もミニマムにすることが期待される。

現在、3種類のIL17抑制薬剤が開発され、治療研究が進められている。
①IL17A抗体（Secukinumab　Novartis社）
②IL17A抗体（Ixekizumab Lilly社）
③IL17A受容体抗体（Brodalumab Amgen社）

その一つ、Secukinumabの効果（PASI75）＝すごく乾癬がよくなる）では、たった3回の注射で90％以上の患者がPASI75を達成する。

PASI90（＝乾癬がほとんどなくなる）でみても、60％の患者で達成されている。

Secukinumabの臨床効果。上の段は「プラセボ（偽薬）」、下の段がSecukinumab。

Ixekizumabの効果（PASI90）。約80％の患者で達成されている。驚異的である。

Brodalumabの臨床効果

印象深かった講演をもう一つ、詳細に紹介いたします。
米国のAnne Bowcock教授の”The genetics of psoriasis: Old risks, novel loci （乾癬の遺伝子研究：昔から言われていた異常、新しく見つかった場所）です。Bowcock教授は、乾癬の原因遺伝子について世界で最初に報告した研究者です。ここでも少し講演スライドを拝借（Bowcock先生、ごめんなさい）。

Bowcock 教授は１９９９年、乾癬家系の詳細な遺伝子調査から第１７染色体に乾癬と関わり深い遺伝子異常があることをみつけ、科学雑誌Scienceに報告した。 21世紀を迎える直前のことであり、遠からず乾癬の原因遺伝子が確定し、完治治療を開発することも夢ではないと、当時期待したものでした。
ところが、次々と関連遺伝子はみつけられるものの（現在は30種類以上）、肝心の原因遺伝子、特定のタンパク、メカニズムは不明のままでした。

Bowcock 教授の息の長い研究は、第17染色体上にあるCARD14と呼ばれるタンパクの、その異常が直接乾癬を起こすことを説き明かしました。CARD14は細胞膜上にあるタンパクで、細胞外で起こる炎症から生じる様々な刺激物質を、細胞の膜から細胞の中へ伝える役割を果たしています。その伝達経路はNFκBを介しています（乾癬ではこの経路が活発に動いていることが、高知大学の佐野教授により解明されました）。

遺伝性膿疱性乾癬患者では、このCARD14遺伝子に点突然変異が起こっていることを発見しました。この点突然変異だけで、特殊タイプではありますが、乾癬の原因が特定されたのです。

点突然変異だけではなく、CARD14遺伝子に起こりやすい変異も、ほかの遺伝子異常（PSORS1、MHC遺伝子）、あるいは環境変化が加わると乾癬を引き起こすことも証明しました。

大変感銘深い講演でした。
会議の模様、IFPA代表者会議の報告は、また後日掲載いたします（『2012年9月教室抄録』をご覧ください）。
ブログ「PHOTO & ESSAY」もご覧ください。

Phase 3-LY2439821 (ixekizumab) for psoriasis and psoriatic arthritis.

October 25, 2013 7:33 am / 2 Comments on Phase 3-LY2439821 (ixekizumab) for psoriasis and psoriatic arthritis.

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

USAN IXEKIZUMAB
PRONUNCIATION ix” e kiz’ ue mab
THERAPEUTIC CLAIM Treatment of autoimmune diseases
CHEMICAL NAMES
1. Immunoglobulin G4, anti-(human interleukin 17A) (human monoclonal LY2439821γ4-chain), disulfide with human monoclonal LY2439821 κ-chain, dimer
2. Immunoglobulin G4, anti-(human interleukin-17A (IL-17, cytotoxic
T-lymphocyte-associated antigen 8)); humanized mouse monoclonal LY2439821 des-Lys446-[Pro227]γ4 heavy chain {H10S>P,CH3107K>-} (133-219′)-disulfide with humanized mouse monoclonal LY2439821 κ light chain, dimer (225-225”:228-228”)-bisdisulfide
MOLECULAR FORMULA C6492H10012N1728O2028S46
MOLECULAR WEIGHT 146.2 kDa

SPONSOR Eli Lilly and Co.
CODE DESIGNATION LY2439821
CAS REGISTRY NUMBER 1143503-69-8

Source	Humanized
Target	IL-17a

Ixekizumab (ix” e kiz’ ue mab)

Phase III Business area: Bio-Medicines

LY2439821 (ixekizumab) is a biologic entity that neutralizes a soluble factor called interleukin-17A (IL-17). LY2439821 is being studied for the treatment of psoriasis and psoriatic arthritis.

Ixekizumab is a humanized monoclonal antibody used in the treatment of autoimmune diseases.^[1]

Ixekizumab was developed by Eli Lilly and Co.

“Statement On A Nonproprietary Name Adopted By The USAN Council: Ixekizumab”.American Medical Association.

Lilly’s Anti-IL-17 Monoclonal Antibody, Ixekizumab, Met Primary Endpoint in Phase II Study in Patients With Chronic Plaque Psoriasis – March 28, 2012

more info

Inflammation represents a key event of many diseases, such as psoriasis, inflammatory bowel diseases, rheumatoid arthritis, asthma, multiple sclerosis,

atherosclerosis, cystic fibrosis, and sepsis. Inflammatory cells, such as neutrophils, eosinophils, basophils, mast cells, macrophages, endothelial cells, and platelets, respond to inflammatory stimuli and foreign substances by producing bioactive mediators. These mediators act as autocrines and paracrines by interacting with many cell types to promote the inflammatory response. There are many mediators that can promote inflammation, such as cytokines and their receptors, adhesion molecules and their receptors, antigens involved in lymphocyte activation, and IgE and its receptors. [0004] Cytokines, for example, are soluble proteins that allow for communication between cells and the external environment. The term cytokines includes a wide range of proteins, such as lymphokines, monokines, interleukins, colony stimulating factors, interferons, tumor necrosis factors, and chemokines. Cytokines serve many functions, including controlling cell growth, migration, development, and differentiation, and mediating and regulating immunity, inflammation, and hematopoiesis. Even within a given function, cytokines can have diverse roles. For example, in the context of mediating and regulating inflammation, some cytokines inhibit the inflammatory response (anti-inflammatory cytokines), others promote the inflammatory response (pro-inflammatory cytokines). And certain cytokines fall into both categories, i.e., can inhibit or promote inflammation, depending on the situation. The targeting of proinflammatory cytokines to suppress their natural function, such as with antibodies, is a well-established strategy for treating various inflammatory diseases.

Many inflammatory diseases are treated by targeting proinflammatory cytokines with antibodies. Most (if not all) of the anti-proinflammatory cytokine antibodies currently on the market, and those currently in clinical trials, are of the IgG class. See, for example, Nature Reviews, vol. 10, pp. 301-316 (2010); Nature Medicine, vol. 18, pp. 736-749 (2012); Nature Biotechnology, vol. 30, pp. 475-477 (2012); Anti-Inflammatory & Anti- Allergy Agents in Medicinal Chemistry, vol. 8, pp. 51-71 (2009);

FlOOO.com/Reports/Biology/content/1/70, F 1000 Biology Reports, 1 :70 (2009); mAbs 4: 1, pp. 1-3 (2012); mAbs 3: 1, pp. 76-99 (2011); clinicaltrials.gov (generally), and

clinicaltrialsregister.eu/ (generally). These IgG antibodies are administered systemically and thus are often associated with unwanted side effects, which can include one or more of, for example, infusion reactions and immunogenicity, hypersensitivity reactions,

immunosuppression and infections, heart problems, liver problems, and others. Additionally the suppression of the target cytokines at non-diseased parts of the body can lead to unwanted effects.

In an attempt to reduce side effects associated with systemic treatment and to eliminate the inconvenience and expense of infusions, an article proposed an oral anti-TNF therapy that could be useful in treating Crohn’ s disease. Worledge et al. “Oral Administration of Avian Tumor Necrosis Factor Antibodies Effectively Treats Experimental Colitis in Rats.” Digestive Diseases and Sciences 45(12); 2298-2305 (December 2000). This article describes immunizing hens with recombinant human TNF and an adjuvant, fractionating polyclonal yolk antibody (IgY, which in chickens is the functional equivalent to IgG), and administering the unformulated polyclonal IgY (diluted in a carbonate buffer to minimize IgY acid hydrolysis in the stomach) to rats in an experimental rodent model of colitis. The rats were treated with 600mg/kg/day of the polyclonal IgY. The uses of animal antibodies and polyclonal antibodies, however, are undesirable.

In a similar attempt to avoid adverse events associated with systemic administration, another group, Avaxia Biologies Inc., describes a topical (e.g., oral or rectal) animal-dervied polyclonal anti-TNF composition that could be useful in treating

inflammation of the digestive tract, such as inflammatory bowel disease. WO2011047328. The application generally states that preferably the polyclonal antibody composition is prepared by immunizing an animal with a target antigen, and the preferably the polyclonal antibody composition is derived from milk or colostrum with bovine colostrums being preferred (e.g., p. 14). The application also generally states that the animal derived polyclonal antibodies could be specific for (among other targets) other inflammatory cytokines (e.g., pp. 6-7). This application describes working examples in which cows were immunized with murine TNF and the colostrum was collected post-parturition to generate bovine polyclonal anti-TNF antibodies (designated as AVX-470). The uses of animal-derived antibodies and polyclonal antibodies, however, are undesirable.

IgA molecular forms have been proposed as treatments for various diseases, most notably as treatments for pollen allergies, as treatments against pathogens, and as treatments for cancer.

For example, one article describes anti-AmbCtl (a ragweed pollen antigen) humanized monomelic IgA and dimeric IgA antibodies made in murine cells (NSO and Sp2/0 cells). The dimeric IgA contains a mouse J-chain. The article proposes that the antibodies may be applied to a mucosal surface or the lower airway to inhibit entry of allergenic molecules across the mucosal epithelium and therefore to prevent the development of allergic response. Sun et al. “Human IgA Monoclonal Antibodies Specific for a Major Ragweed Pollen Antigen.” Nature Biotechnology 13, 779-786 (1995).

Several other articles propose the use of IgA antibodies as a defense against pathogens.

Two articles proposed the use of an anti-streptococcal antigen I II secretory IgA-G hybrid antibody. Ma et al. “Generation and Assembly of Secretory Antibodies in Plants.” Science 268(5211), 716-719 (May 1995); Ma et al. “Characterization of a

Recombinant Plant Monoclonal Secretory Antibody and Preventive Immunotherapy in Humans.” Nature Medicine 4(5); 601-606 (May 1998). The hybrid antibody contains murine monoclonal kappa light chain, hybrid Ig A-G heavy chain, murine J- Chain, and rabbit secretory component. The antibody was made by successive sexual crossing between four transgenic N. tabacum plants and filial recombinants to form plant cells that expressed all four protein chains simultaneously. The parent antibody (the source of the antigen binding regions, is identified as the IgG antibody Guy’s 13. The group proposes that although slgA may provide an advantage over IgG in the mucosal environment, such is not always the case (1998 Ma at p. 604, right column).

A related article identifies the anti-streptococcal antigen I/II secretory IgA-G hybrid antibody, which was derived from Guy’s 13 IgA, as CaroRx. Wycoff. “Secretory IgA Antibodies from Plants.” Current Pharmaceutical Design 10(00); 1-9 (2004). Planet Biotechnology Inc. This related article states that the CaroRx antibody was designed to block adherence to teeth of the bacteria that causes cavities. Apparently, the CaroRx antibody was difficult to purify; the affinity of Protein A for the murine Ig domain was too low and protein G was necessary for sufficient affinity chromatography. Furthermore, the article states that several other chromatographic media had shown little potential as purification steps for the hybrid slgA-G from tobacco leaf extracts. The article also indicates that the authors were unable to control for human-like glycosylation in tobacco, but that such was not a problem because people are exposed to plant glycans every day in food without ill effect.

WO9949024, which lists Wycoff as an inventor, Planet Biotechnology Inc. as the applicant, describes the use of the variable regions of Guy’s 13 to make a secretory antibody from tobacco. The application contains only two examples – the first a working example and the second a prophetic example. Working Example 1 describes the transient production of an anti-S. mutans SA I/III (variable region from Guy’s 13) in tobacco. The tobacco plant was transformed using particle bombardment of tobacco leaf disks. Transgenic plants were then screened by Western blot “to identify individual transformants expressing assembled human slgA” (p. 25). Prophetic Example 2 states that in a transformation system for Lemna gibba (a monocot), bombardment of surface-sterilized leaf tissue with DNA- coated particles “is much the same as with” tobacco (a dicot). The prophetic example also stops at screening by immunoblot analysis for antibody chains and assembled slgA, and states that the inventors “expect to find fully assembled slgA.” [0014] Another article proposed the use of an anti-RSV glycoprotein F IgA antibodies (mlgA, dlgA, and slgA). Berdoz et al. “In vitro Comparison of the Antigen-Binding and Stability Properties of the Various Molecular Forms of IgA antibodies Assembled and Produced in CHO Cells.” Proc. Natl. Acad. Sci. USA 96; 3029-3034 (March 1999). The slgA antibody was made in CHO cells sequentially transfected with chimeric heavy and light chains, human J-Chain, and human secretory component, respectively. Single clones were generated to express the mlgA (clone 22), the dlgA (clone F), and the slgA (clone 6) (p. 3031).

Still other articles proposed, for example: (1) anti-HSV mlgA made in maize (Karnoup et al. Glycobiology 15(10); 965-981 (May 2005)) (which states that at that time there had been little success in the application of IgA class antibodies to therapeutic use because of the difficulty in producing the dimeric form in mammalian cells at economic levels); (2) anti-C. difficile toxin A chimeric mouse-human monomeric and dimeric IgA made in CHO cells (Stubbe et al. Journal of Immunology 164; 1952-1960 (2000)); (3) anti-N. meningitidis chimeric IgA antibodies were produced in BHK cells cotransfected with human J-Chain and/or human secretory component (Vidarsson et al., Journal of Immunology 166; 6250-6256 (2001)); (4) mti-Pseudomonas aeruginosa 06 lipopolysaccharide chimeric mouse/human mlgAl made in CHO cells (Preston et al. Infection and Immunity 66(9); 4137- 4142 (September 1998)); (5) anti-Plasmodium mlgA made in CHO cells (Pleass et al. Blood 102(13); 4424-4429 (December 2003)) (which states that unlike their parental mouse IgG antibodies, the mlgA antibodies failed to protect against parasitic challenge in vivo); and (5) ^^-Helicobacter pylori urease subunit A slgA and dlgA (Berdoz et al. Molecular

Immunology 41(10); 1013-1022 (August 2004)). [0016] For a review article discussing passive and active protection against pathogens at mucosal surfaces, see Corthesy. “Recombinant Immunoglobulin A: Powerful Tools for Fundamental and Applied Research.” Trends in Biotechnology 20(2); 65-71 (February 2002).

Still other articles propose the use of IgA antibodies as a treatment for cancer.

For example, one article describes a Phase la trial of a muring anti-transferrin receptor IgA antibody (Brooks et al. “Phase la Trial of Murine Immunoglobulin A

Antitransferrin Receptor Antibody 42/6.” Clinical Cancer Research 1(11); 1259-1265 (November 1995)). Another article describes a human anti-Ep-CAM mIgA made in BHK (baby hamster kidney) cells (Huls et al. “Antitumor Immune Effector Mechanisms Recruited by Phase Display-Derived Fully Human IgGl and IgAl Monoclonal Antibodies.” Cancer Research 59; 5778-5784 (November 1999)). Still another article describes an anti-HLA Class II chimeric mIgA antibody made in BHK cells (Dechant et al. “Chimeric IgA Antibodies Against HLA Class II Effectively Trigger Lymphoma Cell Killing.” Blood 100(13); 4574- 4580 (December 2002)). Yet other articles describe anti-EGFR mIgA or dlgA antibodies made in CHO, including Dechant et al. “Effector Mechanisms of Recombinant IgA

Antibodies Against Epidermal Growth Factor Receptor.” Journal of Immunology 179; 2936- 2943 (2007), Beyer et al. “Serum- Free Production and Purification of Chimeric IgA

Antibodies.” Journal of Immunology 346; 26-37 (2009) (stating that as of 2009, IgA antibodies have not been commercially explored for problems including lack of production and purification methods), and Lohse et al. “Recombinant Dimeric IgA Antibodies Against the Epidermal Growth Factor Receptor Mediate Effective Tumor Cell Killing.” Journal of Immunology 186; 3770-3778 (February 2011).

For a review article on anti-cancer IgA antibodies, see Dechant et al. “IgA antibodies for Cancer Therapy. ” Critical Reviews in Oncology/Hematology 39; 69-77 (2001); states that compared with infectious diseases, the role of IgA in cancer immunotherapy is even less investigated).

IL17 and IFN-garama inhibition for the treatment of autoimmune inflammation

The IL-17 family of cytokines has been associated with the pathogenesis of autoimmune diseases and is generally blamed for the pathogenic symptoms of autoimmune inflammation. Overexpression of IL-17 is a hallmark for autoimmune diseases like rheumatoid arthritis, systemic lupus erythematomatosus, inflammatory bowel disease, multiple sclerosis, and psoriasis (Yao Z et. al., J Immunol, 155(12), 1995, 5483-6. Chang S H, et.al, Cytokine, 46, 2009, 7-11; Hisakata Yamada et.al, Journal of Inflamm. Res., 3, 2010, 33-44)).

The IL-17 cytokine family comprises six members, out of which IL-17 A and IL-17F are the best characterized. IL-17A and IL-17F exist as homo- as well as as heterodimers (IL-17AA, IL-17AF, IL-17FF). IL-17A and IL-17F are clearly associated with inflammation (Gaffen S H, Cytokine, 43, 2008, 402-407; Torchinsky M B et al, Cell. Mol. Life Sci., 67, 2010, 1407- 1421).

The secretion of IL-17 is predominantly caused by a specific subtype of T helper cells termed TH-17 cells. IL-23, TGFp and IL-6 were shown to be important factors leading to conversion of nai^‘ve CD4+ T-cells to THl 7 cells. It was also reported that TGF and IL-6 potently induce in synergy THl 7 differentiation. Important transcription factors for the secretion of IL-17 from TH17 cells are RORyt and STAT3 (IvanovJ et.al. Cell 126, 2006, 1121-1133). IL-17 induces pro-inflammatory cytokines (IL-6, TNF- and IL-lb) and Chemokines (CXCL1,GCP-2,CXCL8 or IL-8,CINC,MCP-1). It increases the production of nitric oxide prostaglandin E2 and matrix-metalloproteinases. As a consequence of these events neutrophil infiltration, tissue damage and chronic inflammation occurs (PECK A et.al, Clin Immunol., 132(3), 2009, 295-304).

Before the recognition of the importance of IL-17 in autoimmune inflammation, IFN-gamma derived from THl cells was believed to be an important cytokine that drives autoimmune disorders (Takayanagi H et. al. Nature, 408, 2000, 600-605. Huang W. et. al. Arthritis Res. Ther., 5, 2002, R49-R59) The secretion of IFN-gamma is a key feature of the THl effector cell lineage and the secretion is regulated by the transcription factors T-bet and STAT4 (Bluestone JA et. al. Nat Rev Immunol, 11, 2009, 811-6). Infiltration of activated T-cells and elevation of M-CSF, IL-10 and TNF support this notion (Yamanda H et.al Ann. Rheu. Dis., 67, 2008, 1299-1304; Kotake S et.al. Eur. J. Immunol, 35, 2005, 3353-3363).

Recently, a more complex situation was proposed, where hybrid TH17/TH1 cells induced by IL-23 and IL-6 in concert with IL-1 secrete IL-17 and IFN-gamma. These cells are under the control of the transcription factors RORyt and T-bet, confirming the notion, that these are true hybrids of THl and THl 7 cells. It was also demonstrated that these double producing cells are the pathogenic species in IBD and EAE (Buonocore S et.al. Nature, 464, 2010, 1371-5; Ghoreshi K. et. al. Nature, 467, 2010, 967-971).

Compounds which target and suppress both IL-17 and IFN-gamma are predisposed for the treatment of autoimmune disorders.

The effectiveness of blocking IL-17 signaling as therapeutic treatment in autoimmune diseases has already been proven in clinical trials with e.g. monoclonal antibodies against IL- 17A (AIN457, secukinumab; Ly2439821,ixekizumab; RG4934) and/or the IL-17 receptor IL- 17RA (AMG827, brodalumab).

Positive results have been reported for the treatment of rheumatoid arthritis, psoriasis and uveitis (Hueber W et al, Sci. Transl. Med., 2, 2010, 52ra72, DOI: 10.1126/scitranslmed.3001107; van den Berg W B e/ al, Nat. Rev. Rheumatol, 5, 2009, 549-553), ankylosing spondylitis and spondyloarthritides (Song I-H et al, Curr. Opin. Rheumatol., 23, 2011, 346-351).

Secukinumab is currently under investigation in clinical trials for psoriatic arthritis, Behcet disease, uveitits, inflammatory bowel disease, Crohn’s disease, multiple sclerosis (Kopf M et al., Nat. Rev. Drug Disc, 9, 2010, 703-718; Song I-H et al, Curr. Opin. Rheumatol., 23, 2011, 346-351).

Brodalumab, Ixekizumab and RG4934 are currently in clinical trials for the treatment of rheumatoid arthritis, psoriasis and/or psoriatic arthritis (Kopf M et al, Nat. Rev. Drug Disc, 9, 2010, 703-718; clinicaltrials.gov; Medicines in development for skin diseases, 201 1, published by PhRMA, www .phrma. com) .

With regard to blocking of IFN-gamma signaling as therapeutic treatment in autoimmune diseases, the IFN-gamma-specific monoclonal antibody AMG811 is currently under clinical investigations for the treatment of systemic lupus erythematosus (Kopf M et al., Nat. Rev. Drug Disc, 9, 2010, 703-718).

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