New Drug Approvals

Home » FDA 2017 » Netarsudil, Нетарсудил , نيتارسوديل , 奈舒地尔 , ネタルスジル ,

Netarsudil, Нетарсудил , نيتارسوديل , 奈舒地尔 , ネタルスジル ,

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Categories

Blog Stats

  • 4,185,594 hits

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,792 other subscribers

add to any

Share

Netarsudil.pngChemSpider 2D Image | netarsudil | C28H27N3O3

Netarsudil

Molecular Formula: C28H27N3O3
Molecular Weight: 453.542 g/mol

Netarsudil; UNII-W6I5QDT7QI; W6I5QDT7QI; 1254032-66-0; Netarsudil [USAN]; AR-11324 free base

1422144-42-0 (mesylate)   1254032-66-0 (free base)   1253952-02-1 (HCl)

[4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate

4-[(2S)-3-Amino-1-(6-isoquinolinylamino)-1-oxo-2-propanyl]benzyl 2,4-dimethylbenzoate [ACD/IUPAC Name]
Benzoic acid, 2,4-dimethyl-, [4-[(1S)-1-(aminomethyl)-2-(6-isoquinolinylamino)-2-oxoethyl]phenyl]methyl ester
W6I5QDT7QI
Нетарсудил [Russian] [INN]
نيتارسوديل [Arabic] [INN]
奈舒地尔 [Chinese] [INN]
ネタルスジル;
Inventor – Aerie Pharmaceuticals, Inc. 
Approved by US-FDA in December-2017 for dimesylate salt

Image result for NetarsudilImage result for Netarsudil

Netarsudil Mesylate
CAS: 1422144-42-0 (mesylate)
Chemical Formula: C30H35N3O9S2

Molecular Weight: 645.742

1422144-42-0 [RN]
4-[(2S)-3-Amino-1-(6-isoquinolinylamino)-1-oxo-2-propanyl]benzyl 2,4-dimethylbenzoate methanesulfonate (1:2)
Benzoic acid, 2,4-dimethyl-, [4-[(1S)-1-(aminomethyl)-2-(6-isoquinolinylamino)-2-oxoethyl]phenyl]methyl ester, methanesulfonate (1:2)

Netarsudil dimesylate is a light yellow-to-white powder that is freely soluble in water, soluble in methanol, sparingly soluble in dimethyl formamide, and practically insoluble in dichloromethane and heptane.

Netarsudil ophthalmic solution 0.02% is supplied as a sterile, isotonic, buffered aqueous solution of netarsudil dimesylate with a pH of approximately 5 and an osmolality of approximately 295 mOsmol/kg. It is intended for topical application in the eye. Each mL of netarsudil contains 0.2 mg of netarsudil (equivalent to 0.28 mg of netarsudil dimesylate). Benzalkonium chloride, 0.015%, is added as a preservative. The inactive ingredients are: boric acid, mannitol, sodium hydroxide to adjust pH, and water for injection

Netarsudil, also known as AR-11324, is a Rho-associated protein kinase inhibitor. Netarsudil is potential useful for treating glaucoma and/or reducing intraocular pressure. Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms. Netarsudil inhibited kinases ROCK1 and ROCK2 with a Ki of 1 nM each, disrupted actin stress fibers and focal adhesions in TM cells with IC50s of 79 and 16 nM, respectively, and blocked the profibrotic effects of TGF-β2 in HTM cells. Netarsudil produced large reductions in IOP in rabbits and monkeys that were sustained for at least 24 h after once daily dosing, with transient, mild hyperemia observed as the only adverse effect.

Netarsudil (trade name Rhopressa) is a drug for the treatment of glaucoma. In the United States, the Food and Drug Administrationhas approved a 0.02% ophthalmic solution for the lowering of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.[1]

Rho-associated protein kinase (ROCK) is a kinase belonging to the AGC (PKA/ PKG/PKC) family of serine-threonine kinases. It is involved mainly in regulating the shape and movement of cells by acting on the cytoskeleton. ROCK signaling plays an important role in many diseases including diabetes, neurodegenerative diseases such as Parkinson´s disease and amyotrophic lateral sclerosis, pulmonary hypertension and cancer. It has been shown to be involved in causing tissue thickening and stiffening around tumours in a mouse model of skin cancer, principally by increasing the amount of collagen in the tissue around the tumour.

WO 2014144781Image result for Netarsudil

SYNTHESIS

WO2010127329

 

 

CONTINUED………..

PATENT

WO 2014144781

CN 107434780

https://www.google.com/patents/CN107434780A?cl=en

Synthesis of Compound 12

Figure CN107434780AD00153

[0091] The 2,4-dimethyl benzoic acid (1.5g, IOmmol) and a catalytic amount of DMF was added to the toluene and cooled to 2-5 ° C, was added dropwise oxalyl chloride (I.64g, 13_〇1 ), warmed to room temperature after dropwise, stirred overnight, during which a solid gradually dissolved to give a clear solution, evaporated to dryness under reduced pressure to give a yellow oil with dichloromethane (IOml) was dissolved in dichloromethane to give the acid chloride ;

[0092] Compound 11 (3.2g, 7.7mmo 1) and triethylamine (2ml) were added 20ml of dichloromethane, nitrogen, the above prepared acid chloride solution in dichloromethane dropwise at 0-5 ° C the increases after mixing, overnight; TLC (dichloromethane: methanol = 20: 1) to monitor the reaction, completion of the reaction, evaporated to dryness under reduced pressure, and then stirred with saturated sodium carbonate solution, filtered, the filter cake was washed with water 3 times, dried to give 3.9g white solid, i.e. compound 12; purity: 991%, optical purity: 100% (CHIRALPAK AS-H, 0.46cm IDX15cm L, Me0H + 0.1DEA) / C02 = 20/80 (V / V, 2.0ml / min), R-type, Rt = 3 · 253min; S type Rt = 4.3min).

Compound 12 (3.9g) in DCM was added, with stirring to obtain clear solution, was then added dropwise I, a solution of hydrogen chloride in dioxane 15ml 4_ (concentration 4mol / L, 4mol HCl gas dissolved in two IL oxygen six ring), and then stirred for 4 hours at room temperature, rotary evaporated under reduced pressure, and filtered to give 3.65g product as a white solid, was obtained HNMR detectable substance is the AR-13324 hydrochloride, which IHNMR spectrum Referring to FIG. 1 , MS, purity, 99.4%, lHNMR (400MHz, DMS0,300) S (Ppm) c3Il .773 (s, 1H), 9.702 (s, lH), 8.740 (d, lH), 8.560 (d, 1H), 8.469 (d, 1H), 8.360 (d, 1H), 8.280 (s, 3H), 8.158 (dd, lH), 7.777 (d, lH), 7.577 (d, 2H), 7.496 (d, 2H), 7.134 (s, lH), 7.111 (d, lH), 5.281 (s, 2H), 4.504 (q, lH), 3.609 (q, lH), 3.139 (q, lH), 2.483 (s, 3H), 2.302 ( s, 3H).

Example 2

[0097] In this embodiment, the same processing steps except that Compound 12, the other the same as in Example 1.

[0098] Compound 12 processing steps are as follows: The compound is dissolved in 12 (3.9g) 40ml of dichloromethane, followed by dropwise addition of methanesulfonic acid (2g, 21.6mmol), stirred at room temperature overnight, rotary evaporated under reduced pressure, IOOml diethyl ether was added thereto, followed by stirring, a large amount of white solid was filtered, dried to give a white solid (4.54 g of), yield 97.8%, purity 98.2%, the resulting substance was detected IHNMR AR-13324 is the mesylate salt.

CN 107434780
Figure CN107434780AD00171

References

Patent ID

Patent Title

Submitted Date

Granted Date

US9643927 Process for the preparation of kinase inhibitors and intermediates thereof
2015-11-17
2017-05-09
Patent ID

Patent Title

Submitted Date

Granted Date

US2016346269 COMBINATION THERAPY
2016-08-15
US2014275160 COMBINATION THERAPY
2014-03-14
2014-09-18
US2016243105 COMBINATION THERAPY
2016-04-29
2016-08-25
US9415043 COMBINATION THERAPY
2014-03-14
2014-09-18
US2017204065 PROCESS FOR THE PREPARATION OF KINASE INHIBITORS AND INTERMEDIATES THEREOF
2017-03-31
Netarsudil
Netarsudil.svg
Clinical data
Trade names Rhopressa
Synonyms AR-11324
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
UNII
Chemical and physical data
Formula C28H27N3O3
Molar mass 453.54 g·mol−1

REFERENCES

1: Sturdivant JM, Royalty SM, Lin CW, Moore LA, Yingling JD, Laethem CL, Sherman B, Heintzelman GR, Kopczynski CC, deLong MA. Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma. Bioorg Med Chem Lett. 2016 May 15;26(10):2475-80. doi: 10.1016/j.bmcl.2016.03.104. Epub 2016 Apr 1. PubMed PMID: 27072905.

2: Ren R, Li G, Le TD, Kopczynski C, Stamer WD, Gong H. Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms. Invest Ophthalmol Vis Sci. 2016 Nov 1;57(14):6197-6209. doi: 10.1167/iovs.16-20189. PubMed PMID: 27842161; PubMed Central PMCID: PMC5114035.

3: Li G, Mukherjee D, Navarro I, Ashpole NE, Sherwood JM, Chang J, Overby DR, Yuan F, Gonzalez P, Kopczynski CC, Farsiu S, Stamer WD. Visualization of conventional outflow tissue responses to netarsudil in living mouse eyes. Eur J Pharmacol. 2016 Sep 15;787:20-31. doi: 10.1016/j.ejphar.2016.04.002. Epub 2016 Apr 13. PubMed PMID: 27085895; PubMed Central PMCID: PMC5014700.

4: Lin CW, Sherman B, Moore LA, Laethem CL, Lu DW, Pattabiraman PP, Rao PV, deLong MA, Kopczynski CC. Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma. J Ocul Pharmacol Ther. 2017 Jun 13. doi: 10.1089/jop.2017.0023. [Epub ahead of print] PubMed PMID: 28609185.

5: Lu LJ, Tsai JC, Liu J. Novel Pharmacologic Candidates for Treatment of Primary Open-Angle Glaucoma. Yale J Biol Med. 2017 Mar 29;90(1):111-118. eCollection 2017 Mar. Review. PubMed PMID: 28356898; PubMed Central PMCID: PMC5369028.

/////////////Netarsudil, fda 2017, Rhopressa, AR-11324, AR 11324 

CC1=CC(=C(C=C1)C(=O)OCC2=CC=C(C=C2)C(CN)C(=O)NC3=CC4=C(C=C3)C=NC=C4)C


1 Comment

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

DR ANTHONY CRASTO

Follow New Drug Approvals on WordPress.com

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,792 other subscribers
DR ANTHONY MELVIN CRASTO Ph.D

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 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

Personal Links

View Full Profile →

TWITTER

  • RT @IndiaDST: The 2nd SCO Young Scientists Conclave #SCO_YSC is being hosted @jncasr , an autonomous institute of @IndiaDST , at its campus… 8 hours ago
  • RT @SciUp: Our Understanding Polymorphism online course is only a week away! This five-session course aims to give chemists and engineers a… 8 hours ago
  • RT @SciUp: Join us in Boston, US in May to get up-to-date intel on #flowchemistry. Our '5th Flow Chemistry & Continuous Processing' Confer… 8 hours ago
  • RT @SciUp: Join us online for our 'Work Up and Product Isolation' short course on 23-24 February & you will lean how to design simple and p… 8 hours ago
  • RT @thomasraji: Happy Birthday Mummyji !! Thanks for all your support and your invaluable life lessons.😍😍🎂💐💐🤩 You're not getting older...… 8 hours ago
  • RT @GuwahatiNiper: 74वें गणतंत्र दिवस कार्यक्रम की झलकियां। Glimpses of the 74th Republic Day programme. @Pharmadept @rajneeshtingal @bhagw20 hours ago
  • RT @dst_neelima: DST supported NCoE on CCU at IITB was the knowledge partner in the parallel event organised by ETWG G20 on CCUS on 5 th Fe… 20 hours ago
  • RT @dst_neelima: Glad to represent DST India In an International Conference on CCUS organised as a parallel event to Energy Transition Work… 1 day ago
  • Glimpse of 2nd National One Day Symposium on “Drug Discovery Research in India: Current State and Future Prospects… twitter.com/i/web/status/1… 1 day ago
  • RT @africureonline: World Cancer Day is observed annually on February 4th to raise awareness about the impact of cancer on individuals and… 2 days ago
  • RT @CSIRCIMAP: Activity 13: Dr N Kalaiselvi, DG CSIR & Secretary, DSIR under #CSIR_OneWeekOneLab inaugurated the ‘High Throughput Instrumen… 2 days ago
  • Career counseling to pharma students, At Govindrao Nikam College Of Pharmacy Sawarde,Tal - Chiplun, Ratnagiri, Mh 4… twitter.com/i/web/status/1… 2 days ago
  • RT @bluetech_media: We are proud to welcome Dr.@Anthony Melvin Crasto Advisor Africure Pharma, Global A WDT API INT RnD, Ex Glenmark LS, Wo… 3 days ago
  • Meet me at Global PHT 2023. as Guest of honor and speaker 𝐆𝐥𝐨𝐛𝐚𝐥 𝐏𝐡𝐚𝐫𝐦𝐚 𝐇𝐞𝐚𝐥𝐭𝐡𝐜𝐚𝐫𝐞 𝐓𝐞𝐜𝐡𝐧𝐨𝐥𝐨𝐠𝐲 𝐄𝐱𝐩𝐨 & 𝐒𝐮𝐦𝐦𝐢𝐭 𝟐𝟎𝟐𝟑… twitter.com/i/web/status/1… 4 days ago
  • Lifetime achievement award nomination at GlobalPHT 2023 𝐆𝐥𝐨𝐛𝐚𝐥 𝐏𝐡𝐚𝐫𝐦𝐚 𝐇𝐞𝐚𝐥𝐭𝐡𝐜𝐚𝐫𝐞 𝐓𝐞𝐜𝐡𝐧𝐨𝐥𝐨𝐠𝐲 𝐄𝐱𝐩𝐨 & 𝐒𝐮𝐦𝐦𝐢𝐭 (𝐆𝐥𝐨𝐛𝐚𝐥… twitter.com/i/web/status/1… 4 days ago

bloglovin

Follow my blog with Bloglovin The title of your home page You could put your verification ID in a comment Or, in its own meta tag Or, as one of your keywords Your content is here. The verification ID will NOT be detected if you put it here.
%d bloggers like this: