New Drug Approvals

Home » Posts tagged 'IND Filed'

Tag Archives: IND Filed

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

Blog Stats

  • 2,620,816 hits

Flag and hits

Flag Counter

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

Join 2,416 other followers

Follow New Drug Approvals on WordPress.com

Categories

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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

Join 2,416 other followers

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 GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 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, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, 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 30 year tenure till date Dec 2017, 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 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, 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 19 lakh plus views on New Drug Approvals Blog in 216 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

Personal Links

Verified Services

View Full Profile →

Categories

Flag Counter
Advertisements

SM 934, β-Aminoarteether maleate


str1

STR1

SM 934

  • Ethanamine, 2-[(decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-yl)oxy]-, [3R-(3α,5aβ,6β,8aβ,9α,10α,12β,12aR*)]-, (Z)-2-butenedioate (1:1)
  • 3,12-Epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin, ethanamine deriv.
  • SM 934
  • β-Aminoarteether maleate
CAS 133162-25-1
MF C17 H29 N O5 . C4 H4 O4
Ethanamine, 2-[(decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-yl)oxy]-, (3R,5aS,6R,8aS,9R,10S,11aR)-, (2Z)-2-butenedioate (1:1)

TLR7/9 signal transduction modulator

IND FILED

2.5 and 5 mg/kg, ig (MRL/lpr mice);
10 mg·kg−1·d−1, ig (NZB/W F1 mice)

Autoimmune diseases; SLE

SM934, an artemisinin derivative, possesses potent antiproliferative and antiinflammatory properties.

str1

In the present study, we investigated the immunosuppressive effects and underlying mechanisms of beta-aminoarteether maleate (SM934), a derivative of artemisinin, against T cell activation in vitro and in vivo. In vitro, SM934 significantly inhibited the proliferation of splenocytes induced by concanavalin A (Con A), lipopolysaccharide (LPS), mixed lymphocyte reaction (MLR), and anti-CD3 plus anti-CD28 (anti-CD3/28). SM934 significantly inhibited interferon (IFN)-gamma production and CD4(+) T cell division stimulated by anti-CD3/28. SM934 also promoted apoptosis of CD69(+) population in CD4(+) T cells stimulated by anti-CD3/28. Furthermore, SM934 inhibited interleukin (IL)-2 mediated proliferation and survival through blocking Akt phosphorylation in activated T cells. In ovalbumin (OVA)-immunized mice, oral administration of SM934 suppressed OVA-specific T cell proliferation and IFN-gamma production. SM934 treatment also significantly inhibited the sheep red blood cell (SRBC)-induced delayed type hypersensitivity (DTH) reactions in mice. Taken together, SM934 showed potent immunosuppressive activities in vitro and in vivo. Our results demonstrated that SM934 might be a potential therapeutic agent for immune-related diseases.

PATENT

http://www.google.co.in/patents/EP0362730A1?cl=en

Figure imgb0005

Figure imgb0006

PAPER

Volume 9, Issues 13–14, December 2009, Pages 1509–1517

Inflammatory Mediators Long Term after Sulfur Mustard Exposure (Sardasht-Iran Cohort Study)

SM934, a water-soluble derivative of arteminisin, exerts immunosuppressive functions in vitro and in vivo

  • a State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China
  • b Department of Synthetic Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China
  • c Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People’s Republic of China

  • Hou LF, He SJ, Wang JX, Yang Y, Zhu FH, Zhou Y, et al. SM934, a water-soluble derivative of arteminisin, exerts immunosuppressive functions in vitro and in vivo. Int Immunopharmacol 2009; 9: 1509–17. | Article |
  • Hou LF, He SJ, Li X, Yang Y, He PL, Zhou Y, et al. Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses. Arthritis Rheum 2011; 63: 2445–55. | Article
  • Hou LF, He SJ, Li X, Wan CP, Yang Y, Zhang XH, et al. SM934 treated lupus-prone NZB x NZW F1 mice by enhancing macrophage interleukin-10 production and suppressing pathogenic T cell development. PLoS One 2012; 7: e 32424.
  • Wu Y, He S, Bai B, Zhang L, Xue L, Lin Z, et al. Therapeutic effects of the artemisinin analog SM934 on lupus-prone MRL/lpr mice via inhibition of TLR-triggered B-cell activation and plasma cell formation. Cell Mol Immunol 2015 Mar 16. doi: 10.1038/cmi.2015.13. [Epub ahead of print].

/////////TLR7/9 signal transduction modulator, SM 934, IND FILED, 133162-25-1, β-Aminoarteether maleate

[C@@H]3(OC1O[C@@]4(CCC2C1(C(CC[C@H]2C)[C@H]3C)OO4)C)OCCN.C(=C/C(=O)O)/C(=O)O

Advertisements

CN-128 for the treatment of thelassemia and iron overload


Figure imgf000011_0002

STR3

CN-128

(R)-3-Hydroxy-1-(1-hydroxy-3-benzyl propyl-2-)2-methyl pyridine-4(1H)-one

IND Filing

CN-128 is potentially for the treatment of thelassemia and iron overload.

Zhejiang University, 浙江大学

CAS No. 1335282-04-6

C15 H17 N O3, 4(1H)​-​Pyridinone, 3-​hydroxy-​1-​[(1R)​-​1-​(hydroxymethyl)​-​2-​phenylethyl]​-​2-​methyl-
Molecular Weight, 259.30

Many diseases in humans and animals are caused by excessive accumulated metals, such as iron. Among such diseases, excess iron is accumulated in various tissues, which is called iron overload disorders, formerly known as siderosis Haemorrhagic. Excess iron has the following sources: 1) long-term blood transfusion; 2) the gastrointestinal system absorbing excess iron, because stimulated by diseases such as anemia. It is necessary to repeat transfusion for some patients with severe anemia, for example, β-thalassemia, as well as other anemia requiring transfusion therapy. Excessive iron absorption from the gastrointestinal tract usually occurs in hemochromatosis patients and in anemia patients who do not require blood transfusion, such as thalassemia intermedia. If iron overload disease is not treated, it will result in severe tissue damage, especially the liver, heart and endocrine organs, and ultimately lead to death. Iron chelators can remove and clear excess iron from such organs, relieve symptoms and reduce the corresponding mortality.

Desferrioxamine (DFO) is an effective iron chelator for a long time. However, in the treatment of the diseases mentioned above, the biggest disadvantage regarding DFO and its salts is its poor oral absorption capability. So, administration is achieved with a slow injection method (8∼12h/day), patients need to wear a portable drug delivery device during treatment, such as mounting the syringe on a mechanical pressing device. This method is inconvenient, and also expensive, which largely limits the utilization of DFO, especially for thalassemia-prone areas, such as Mediterranean, Middle East, and India &South East Asia, it plays no role in treatment of malaria in world-wide and sickle cell anemia in some African countries, which is a very serious problem to the populations there. Image loading...

UK Patent No. 2, 13, 807, US Patent No. 4, 585, 780 and other scientific research have reported the treatment of iron overload symptoms by using 3-hydroxypyridin-4-one derivatives, especially in some pathological symptoms, such as thalassemia, sickle cell anemia, aplastic anemia in children, and idiopathic hemochromatosis, usually, treatment of the first three diseases includes frequent regular blood transfusion. 3-Hydroxypyridin-4-one derivatives, especially CP20 (commercial named Ferriprox) is employed to treat systemic iron overload disorders, and also to treat certain diseases associated with local iron overload distribution, although such patients do not show symptoms of systemic iron overload, i.e. inhibition free radical mediated reactions caused by excess iron ions in certain neurodegenerative diseases and cancer diseases. A serious limitation of CP20 is that the hydroxyl group at 3′ position is vulnerable to glycosylation, which reduces the half-life of this compound (approximately 2∼3 h). So it requires a high dosage, which is associated with obvious side effects. Image loading...

EP0120669 discloses compounds with a 3-hydroxypyrid-4-one in which the H attached to the N atom is substituted by an aliphatic acyl group, or an aliphatic hydrocarbon group, these groups can be further substituted, but not by aromatic groups and their use against illnesses related to iron overload. Molenda et al. disclose in Journal of Medicinal Chemistry 1994, 37, pages 4363-4370 chiral 3-hydroxy-pyridin-4-one compound 6 as enhancing iron excretion.

US Patent No. 6, 465, 604 described a series of 3,5-diphenyl-1,2,4-triazole compounds, wherein including Exjade (commercial name), which has strong affinity to Fe(III), However, its active groups contain two negatively charged oxygen ions and a carboxyl group; it is a tridentate ligand while chelating Fe(III), which forms a Fe-L2 type complex, possessing three unit negative charges itself, that is bad for their discharge from cells/tissues. Moreover, one of the active groups is a nitrogen atom with a lone pair of electrons, Exjade may have a negative effect on the balance of Zn(II) in vivo, at the same time because it has two phenolic hydroxyl groups in different positions (forming intramolecular hydrogen bonds structure similar to cis/trans isomerization), it can be complexed to several zinc ions to form high molecular weight polymers complexes, which is not conducive to its discharge from the cells either. Image loading...

Absorption, distribution, metabolism and excretion of chiral medicines are largely related to the 3D structures of their chiral centers. For drug absorption, chiral compounds entering cells via active transport mechanism are usually carried by special transport proteins, their recognition of enantiomers can be different, resulting in different absorption of enantiomers. For drug distribution, the binding effects of plasma protein and tissues are also somewhat stereoselective, leading to different in vivo distribution of enantiomers; for stereoselective of drug metabolism refers to when the substrate is biotransformated, the pathway and speed of enantiomer metabolism by biological systems can be different. One enantiomer may show ascendant metabolism, and therefore it is of great significance to the indicators including drug transformation and in vivo half-life. Glomerular filtration, tubular secretion and reabsorption of chiral drugs to clear the chiral drugs, having stereoselectivity, while the glomerular filtration rate is closely related to drug’s selectivity to binding plasma protein, so discharge style of enantiomers (urine / feces percentage) and the rate is also different.

Therefore, the qualitative difference of the interactions of a pair of enantiomers with various binding sites may exist or not, and the quantitive difference may exist (strong or weak), which results in the different activities between enantiomers. Thus the selection of optical enantiomers for medical use, requires a comprehensive study of metabolic activity, toxicology and pharmacokinetic properties etc. Thus the chiral nature of the 3-hydroxypyridin-4-one derivatives described in this patent has an important role on in vivo iron chelation.

The effectiveness of many oral 3-hydroxy-4-one derivatives drugs are subject to metabolic reaction of the 3-hydroxy moiety, which may be quickly glycosylated (see Reaction I). The hydroxypyridone after glycosylation loses the ability to chelate Fe(III). We can effectively inhibit glycosylation reaction by introducing hydroxyl groups to alkyl substituted residues on the pyridine ring. In addition, the partition coefficient of 3-hydroxy-pyridin-4-one derivatives has a great impact on the in vivo distribution and toxic effects. We have introduced various alkyl groups to the chiral point of the compound, in order to modify their lipophilicity, i.e. a phenyl group connected to the chiral point in compound IV-b while in IV-a it is a methyl group, and thus compound IV-b is relatively more lipophilic, and easier to penetrate through cell membranes of various tissues and critical barriers such as the blood-brain barrier and the placental barrier, thus affecting its in vivo distribution. Thus increase of hydroxyl groups can affect the intestinal absorption capacity, by introducing a large alkyl group, intestinal absorption of 3-hydroxy-pyridin-4-one derivatives can be enhanced. Image loading...

Reaction I

Image loading...

scheme is as follows: Image loading... Image loading...

Example7. (R)-3-Hydroxy-1-(1-hydroxy-3-benzyl propyl-2-)2-methyl pyridine-4(1H)-one, Number: CN128.

Image loading...

60 g 3-phenyloxy-2-methyl-4H-pyran-one(Example 1) was dissolved in 150 mL n-butanol, then 83.7 g D-phenylalaninol was added in. After thoroughly mixing, the solution was refluxed at 118°C for 36 h. After cooling and filtration, products were purified by silica gel column chromatography with Eluent ethanol: acetic ester=1:40. After Elution, light brown solid was obtained after rotary evaporation, which was then dissolved into 150 mL ethanol and 15 mL water, then it was hydrogenated and debenzylated with 5% Pd/C as catalyst, the solvent was removed under rotary evaporation, the remaining solid was recrystallized with methanol and ether, leading to 25.25 g light yellow solid. The yield was 35.1%. The free alkali’s 1HNMR (DMSO-d6): δ 2.00 (s, 3H), 2.98 (dd, J1=14, J2=5.5, 1H), 3.11 (dd, J1=14, J2=5, 1H), 3.73 (m, 2H), 4.54 (m, 1H), 6.21 (d, J=7, 1H), 7.17 (m, 5H), 7.87 (d, J=7.5, 1H).

PATENT

CN 102190644

http://www.google.com/patents/CN102190644B?cl=en

Zhejiang University

\\\\\\\\\\\\CN-128 , ind filed,  thelassemia,  iron overload, zhejiang
c1ccc(cc1)CC(N\2/C=C\C(/C(=C/2C)O)=O)CO

New “mTOR” inhibitor from Exelixis, Inc., XL 388


XL 388

 A Novel Class of Highly Potent, Selective, ATP-Competitive, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin (mTOR)

Benzoxazepine-Containing Kinase Inhibitor

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone
 [7-​(6-​amino-​3-​pyridinyl)​-​2,​3-​dihydro-​1,​4-​benzoxazepin-​4(5H)​-​yl]​[3-​fluoro-​2-​methyl-​4-​(methylsulfonyl)​phenyl]​-Methanone,
(7-(6-Aminopyridin-3-yl)-2,3-dihydrobenz[f][1,4]oxazepin-4(5H)-yl)(3-fluoro-2-methyl-4-(methylsulfonyl)phenyl)methanone
MW 455.50, CAS 1251156-08-7, MF C23 H22 F N3 O4 S
Exelixis, Inc. INNOVATOR, IND Filed
½H2O
C23H22FN3O4S.½H2O ,  Molecular Weight: 464.51
MONO HYDROCHLORIDE…..CAS 1777807-51-8, [7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone Hydrochloride (1·HCl)
TLC Rf = 0.33 (Dichloromethane:Methanol [95:5])
Potent and selective mTOR inhibitor (IC50 = 9.9 nM). Inhibits mTOR activity in an ATP-competitive manner. Exhibits >300-fold selectivity for mTOR over PI 3-K and a range of other kinases. Displays antitumor activity in athymic nude mice implanted with tumor xenografts.
SYNTHESIS
 
 CLICK ON IMAGE FOR CLEAR VIEW……………..
 
Tyrosine kinases are important enzymes for signal transduction in cells. Therefore, they are often targets for the treatment of diseases that are caused by dysregulation of cellular processes, such as cancers. Mammalian target of rapamycin (mTOR) is a kinase in the phosphatidylinositol-3-kinase (PI3K) family of enzymes and is implicated in the regulation of cell growth and proliferation. Various inhibitors of mTOR have been explored as possible agents for treatment of various cancers
The mammalian target of rapamycin (mTOR) is a large protein kinase that integrates both extracellular and intracellular signals of cellular growth, proliferation, and survival. Both extracellular mitogenic growth factor signaling from cell surface receptors and intracellular signals that convey hypoxic stress, energy, and nutrient status converge at mTOR. mTOR exists in two distinct multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
mTORC1 is a key mediator of translation and cell growth, via its substrates p70S6 kinase (p70S6K) and eIF4E binding protein 1 (4E-BP1), and promotes cell survival via the serum and glucocorticoid-activated kinase (SGK), whereas mTORC2 promotes activation of prosurvival kinase AKT. mTORC1, but not mTORC2, can be inhibited by an intracellular complex between rapamycin and FK506 binding protein (FKBP). However, rapamycin–FKBP may indirectly inhibit mTORC2 in some cells by sequestering mTOR protein and thereby inhibiting assembly of mTORC2.
Given the role of mTOR signaling in cellular growth, proliferation, and survival as well as its frequent deregulation in cancers, several rapamycin analogues (rapalogues) that are selective allosteric mTORC1 inhibitors have been extensively evaluated in a number of cancer clinical trials.
Demonstrated clinical efficacy for rapalogues is currently limited to patients with advanced, metastatic renal cell carcinoma (RCC) despite extensive development efforts.
This result is likely attributed not only to a lack of inhibition of mTORC2 by rapalogues that leads to upregulation of Akt through a negative feedback loop, but also to only partial inhibition of mTORC1.Therefore, ATP-competitive mTOR inhibitors that should simultaneously inhibit both mTORC1 and mTORC2 may offer a clinical advantage over rapalogues.
As a key component of the phosphoinositide 3-kinase-related kinase (PIKK) family, which is comprised of phosphoinositide 3-kinases (PI3Ks), DNA-PK, ATM, and ATR, mTOR shares the highly conserved ATP binding pockets of the PI3K family with sequence similarity of 25% in the kinase catalytic domain.
In light of this fact, it is not surprising that many of the first reported ATP-competitive mTOR inhibitors such as BEZ235 and GDC-0980 also inhibited PI3Ks. PI3Ks are responsible for the production of 3-phosphoinositide lipid second messengers such as phosphatidylinositol 3,4,5-triphosphate (PIP3), which are involved in a number of critical cellular processes, including cell proliferation, cell survival, angiogenesis, cell adhesion, and insulin signaling.
Therefore, the development of ATP-competitive mTOR inhibitors that are selective over PI3Ks may offer an improved therapeutic potential relative to rapalogues as well as dual PI3K/mTOR inhibitors. Recently, several selective ATP-competitive mTOR inhibitors such as Torin 2 and AZD8055  have been reported with sufficient promise to warrant clinical trials.

PATENT

WO 2010118208

Example 2:

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-l,4-benzoxazepin-4(5H)-yl] [3-fluoro- 2-methyl-4-(methylsulfonyl)phenyl]methanone

Figure imgf000250_0001

tørt-Butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[/] [l,4]oxazepine-4(5H)- carboxylate. To a mixture of 4-(te/t-butoxycarbonyl)-2,3,4,5- tetrahydrobenzo[/][l,4]oxazepin-7-ylboronic acid (1.52 g, 5.2 mmol), prepared as described in Reference Example 5, 2-amino-5-bromopyridine (900 mg, 5.2 mmol), and potassium carbonate (1.73 g, 12.5 mmol) in 1 ,2-dimethoxyethane/water (30 mL/10 mL) was added tetrakis(triphenylphosphine)palladium(0) (90 mg, 1.5 mol%) and the reaction mixture was purged with nitrogen and stirred at reflux for 3 h. The reaction was cooled to rt, diluted with water/ethyl acetate (50 mL/50 mL), and the separated aqueous layer was extracted with ethyl acetate. The resulting emulsion was removed by filtration. The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure, and the residue was triturated with toluene for 1 h. The resulting off-white solid was isolated by filtration to give the desired product (1.37 g, 77 %) as an off-white solid. MS (EI) for Ci9H23N3O3: 342 (MH+).

5-(2,3,4,5-Tetrahydrobenzo[/] [l,4]oxazepin-7-yl)pyridine-2-amine. To a stirred solution of tert-butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[/][l,4]oxazepine- 4(5H)-carboxylate (1.36 g, 3.98 mmol) in 1,4-dioxane (5 mL) was added 4 N hydrogen chloride in 1 ,4-dioxane (5 mL) and the reaction mixture was stirred at rt overnight. The reaction was concentrated on a rotary evaporator and the residue was triturated with ether. The solid was isolated by filtration. This solid was dissolved in water (5 mL) and made basic with 5 N sodium hydroxide to pH 11-12. The brownish sticky oil that aggregated at the bottom was isolated and the aqueous layer was extracted with 5 % methanol in ethyl acetate. The extracts were dried with sodium sulfate and concentrated on a rotary evaporator. The brownish sticky oil was dissolved with a mixture of methanol/ethyl acetate, combined with the isolated organic residue and concentrated under reduced pressure to give a yellow solid. This solid was triturated with dichloromethane (10 mL) for 1 h and a yellow solid was isolated by filtration and dried under high vacuum to give amine the desired product (920 mg, 96 %). MS (EI) for Ci4Hi5N3O: 242 (MH+).

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-l,4-benzoxazepin-4(5H)-yl][3-fluoro-2- methyl-4-(methylsulfonyl)phenyl]methanone.

To a stirred suspension of 5-(2, 3,4,5- tetrahydrobenzo[/][l,4]oxazepin-7-yl)pyridine-2-amine (85 mg, 352 μmol) and triethylamine (54 μL, 387 μmol) in dichloromethane (10 mL) was added 3-fluoro-2-methyl-4- (methylsulfonyl)benzoyl chloride (91 mg, in 3 mL of dichloromethane), prepared as described in Reference Example 1, at 0 0C for 2 h. After stirring for an additional 1 h at rt, the reaction mixture was diluted with water (5 mL) and the separated aqueous layer was extracted with dichloromethane. The combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure to give a light-yellow solid that was purified via silica gel chromatography to give the desired product (113 mg, 70%) as a white solid.

1H NMR (400 MHz, DMSO-d6): δ 8.24-8.03 (dd, IH), 7.79-7.71 (m, IH), 7.71-7.69 (dd, 0.5H), 7.57-7.57 (d, 0.5H), 7.44-7.40 (m, 1.5H), 7.29-7.19 (dd, IH), 7.05-7.01 (dd, IH), 6.64-6.63 (d, 0.5H), 6.54-6.45 (dd, IH), 6.06 (s, 2H), 4.93-4.31 (m, 2H), 4.31-3.54 (m, 4H), 3.37-3.36(d, 3H), 2.12-1.77 (d, 3H).

MS (EI) C23H22FN3O4S: 456 (MH+).

PAPER

Journal of Medicinal Chemistry (2013), 56(6), 2218-2234.
J. Med. Chem., 2013, 56 (6), pp 2218–2234
DOI: 10.1021/jm3007933
Abstract Image

A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.

(7-(6-Aminopyridin-3-yl)-2,3-dihydrobenz[f][1,4]oxazepin-4(5H)-yl)(3-fluoro-2-methyl-4-(methylsulfonyl)phenyl)methanone (28)

1H NMR (400 MHz, DMSO-d6): δ (rotamers are observed) 8.24 and 8.03 (d, J = 2.4 Hz, 1H), 7.77 and 7.72 (t, J = 7.6 Hz, 1H), 7.71–7.39 (m, 2H), 7.57 and 6.63 (d, J = 2.4 Hz, 1H), 7.28 and 7.19 (d, J = 7.6 Hz, 1H), 7.04 and 7.02 (d, J = 8.0 Hz, 1H), 6.52 and 6.46 (d, J = 8.8 Hz, 1H), 6.05 (br s, 2H), 4.93–4.31 (m, 2H), 4.28–3.56 (m, 4H), 3.37 and 3.34 (s, 3H), 2.12 and 1.77 (d,J = 1.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): δ 167.3, 167.2, 166.6, 166.6, 158.9, 158.9, 158.4, 158.4, 157.4, 157.2, 155.9, 155.8, 145.4, 145.1, 145.1, 144.0, 143.9, 135.0, 134.7, 132.9, 132.8, 129.4, 129.2, 128.2, 128.2, 128.1, 128.0, 127.0, 126.9, 126.8, 125.9, 125.6, 125.4, 123.6, 123.5, 123.3, 123.1, 122.8, 122.0, 122.0, 121.9, 121.9, 121.2, 120.7, 107.8, 107.8, 70.9, 70.8, 51.1, 51.1, 47.4, 46.5, 43.5, 43.5, 43.5, 43.4, 11.0, 10.9, 10.7, 10.6. IR (KBr pellet): 1623, 1487, 1457, 1423, 1385, 1314, 1269, 1226, 1193, 1144, 1133, 1054, 1031, 962, 821, 768 cm–1. Mp: 204–205 °C. MS (EI): m/z for C23H22FN3O4S, 456.0 (MH+). High-resolution MS (FAB MS using glycerol as the matrix): m/z calcd for C23H22FN3O4S 456.13878, found 456.13943.

PATENT

    SYNTHETIC EXAMPLES
      Reference Example 13-Fluoro-2-methyl-4-(methylsulfonyl)benzoyl chloride

    • Figure US20100305093A1-20101202-C01052
    • 1-Bromo-3,4-difluoro-2-methylbenzene. To a stirred mixture of 2,3-difluorotoluene (1.9 g, 14.8 mmol) and iron (82.7 mg, 1.48 mmol) in chloroform (10 mL) at rt was added bromine (76 μL, 14.8 mmol) over 2 h. The resulting mixture was stirred at rt overnight. Excess water (10 mL) was added and the reaction mixture was diluted with ether (20 mL). The separated organic layer was washed with aqueous sodium thiosulfate, brine, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was distilled to give the desired product (2.49 g, 81%) as a colorless oil.
    • 3,4-Difluoro-2-methylbenzoic acid. To a stirred solution of 1-bromo-3,4-difluoro-2-methylbenzene (940 mg, 4.54 mmol) in tetrahydrofuran (5 mL) was added isopropylmagnesium bromide (3.0 mL, 6.0 mmol) over 1 h at 0° C. The resulting mixture was stirred at rt for 24 h. Carbon dioxide (CO2), generated from dry ice, was introduced to the reaction mixture over 2 h and the resulting mixture was stirred for an additional 30 min. The reaction mixture was quenched with addition of an excess amount of water (5 mL) and the tetrahydrofuran was removed on a rotary evaporator. The resulting aqueous layer was diluted with water (5 mL) and acidified with concentrated hydrochloric acid to pH 1-2. The white precipitate was filtered and washed with water and cold hexanes and dried under high vacuum to give the desired product (630 mg, 81%) as a white powder. MS (EI) for C8H6F2O2: 171 (MH).
    • 3-Fluoro-2-methyl-4-(thiomethyl)benzoic acid. To a stirred solution of acid 3,4-difluoro-2-methylbenzoic acid (700 mg, 4.1 mmol) in dimethylsulfoxide (5 mL) was added powdered potassium hydroxide (274 mg, 4.9 mmol) and the mixture was stirred at rt for 30 min. Sodium thiomethoxide (342 mg, 4.9 mmol) was added to the mixture and the resulting mixture was stirred at 55-60° C. for 4 h. Additional powdered potassium hydroxide (70 mg, 1.2 mmol), sodium thiomethoxide (60 mg, 0.8 mmol), and dimethylsulfoxide (2 mL) were added to the reaction mixture. After stirring for 4 h, the mixture was cooled to 0° C. and quenched with excess water (10 mL). The resulting suspension was acidified at 0° C. with concentrated hydrochloric acid to pH 1-2. The white precipitate was collected by suction filtration, washed with water and dried under vacuum overnight to give the desired product (870 mg, 100%). The intermediate sulfide was used in the next step without further purification. MS (EI) for C9H9FO2S: 199.1 (MH).
    • 3-Fluoro-2-methyl-4-(methylsulfonyl)benzoic acid. To a stirred suspension of 3-fluoro-2-methyl-4-(thiomethyl)benzoic acid in an acetone/water (1 mL/10 mL) mixture was added sodium hydroxide (330 mg, 8.25 mmol) and sodium bicarbonate (680 mg, 8.1 mmol). Oxone (˜4 g) was added portionwise to the reaction mixture at 0° C. over 2 h. The reaction was monitored by LC/MS. Concentrated hydrochloric acid was added to adjust the pH 2-3 and the white precipitate was collected by suction filtration, washed with water, and dried under vacuum. Dried precipitate was suspended in water (10 mL), stirred vigorously at rt for 1 h, filtered, washed with water, and hexanes and dried under vacuum to give the desired product (886 mg, 94%) as a white powder. MS (EI) for C9H9FO4S: 231 (MH).
    • 3-Fluoro-2-methyl-4-(methylsulfonyl)benzoyl chloride. A mixture of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid (860 mg, 3.7 mmol) in thionyl chloride (10 mL) was heated to reflux for 3 h. (the reaction mixture became homogenous). The reaction mixture was concentrated on a rotary evaporator to give the crude acid chloride. This acid chloride was triturated with dichloromethane (2 mL) and concentrated under reduced pressure. The trituration process was repeated 3 times until the product (900 mg, 98%) was obtained as a white powder.

Reference Example 2Ethyl 4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoate hydrochloride salt

  • Figure US20100305093A1-20101202-C01053
  • 4-(ethoxycarbonyl)phenylboronic acid (22.16 g, 114 mmol), tert-butyl 7-bromo-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-carboxylate (34.08 g, 104 mmol), prepared as described in Reference Example 4, Pd(dppf)Cl2 and TEA (21 g, 208 mmol) were combined in a mixture of dioxane (200 mL) and water (20 mL). The reaction mixture was heated to 90° C. for 2 h, then cooled and the solvent removed. Purification of the residue by silica chromatography gave the desired product ester (31.3 g, 69% yield).
  • To the solution of tert-butyl 7-(4-(ethoxycarbonyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (10.3 g, 25.93 mmol) in MeOH (120 mL) was added a solution of 4 N HCl in dioxane (50 mL). The reaction mixture was heated to 50° C. for 3 h (monitored by LC/MS). The reaction mixture was allowed to cool to rt. Ethyl 4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoate as the hydrochloride salt (8.8 g, 99% yield) was collected by suction filtration.
      Reference Example 4tert-Butyl-7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

    • Figure US20100305093A1-20101202-C01055
    • tert-Butyl-5-bromo-2-hydroxybenzyl(2-hydroxyethyl)carbamate. Commercially-available 5-bromo-2-hydroxybenzaldehyde (4.0 g, 10 mmol) and 2-aminoethanol were combined in THF/MeOH (100 mL, 10:1) and sodium borohydride (0.76 g, 2.0 mmol) was added with stirring. The resulting reaction mixture was stirred at 40° C. for 4 h, concentrated on a rotary evaporator then diluted with EtOAc (50 mL) and saturated NaHCO3 (30 mL). To this suspension was added di-tert-butyl dicarbonate (2.83 g, 13 mmol). The mixture was stirred at rt overnight. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated on a rotary evaporator. Hexane was subsequently added to the crude reaction product which resulted in the formation of a white solid. This slurry was filtered to obtain the desired product (6.8 g, 98%) as a white solid. MS (EI) for C14H20BrNO4, found 346 (MH+).
    • tert-Butyl-7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate. tert-Butyl-5-bromo-2-hydroxybenzyl(2-hydroxyethyl)carbamate (3.46 g, 10 mmol) and triphenylphosphine (3.96 g, 15 mmol) were combined in DCM (100 mL) and diisopropyl azodicarboxylate (3.03 g, 15 mmol) was added. The resulting reaction mixture was stirred at rt for 12 h. The reaction mixture was washed with water, dried, filtered, and concentrated on a rotary evaporator. The resulting crude product was purified via silica gel chromatography eluting with 8:2 hexane/ethyl acetate to give the desired product (1.74 g, 53%) as a white solid. MS (EI) for C14H18BrNO3, found 328 (MH+).

Reference Example 54-(tert-Butoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-ylboronic acid

  • Figure US20100305093A1-20101202-C01056
  • To a stirred solution of tert-butyl-7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (10 g, 30.5 mmol), prepared as described in Reference Example 4, and triisopropylborate (9.1 mL, 40 mmol) in dry tetrahydrofuran (100 mL) was added dropwise n-butyllithium in tetrahydrofuran (1.6 M, 25 mL, 40 mmol) while maintaining the temperature below −60° C. Upon completion of addition, the reaction mixture was stirred for 30 min, then quenched with 1 N aqueous hydrochloric acid (35 mL) and allowed to warm to rt. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated on a rotary evaporator. Hexane was subsequently added to the crude reaction product which resulted in the formation of a white solid. This slurry was stirred for 1 h and filtered to obtain 4-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-ylboronic acid (8.6 g, 95%) as a white solid. MS (EI) for C14H20BNO5: 194 (M-Boc).
    Example 2[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone

  • Figure US20100305093A1-20101202-C01076
  • tert-Butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate. To a mixture of 4-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-ylboronic acid (1.52 g, 5.2 mmol), prepared as described in Reference Example 5, 2-amino-5-bromopyridine (900 mg, 5.2 mmol), and potassium carbonate (1.73 g, 12.5 mmol) in 1,2-dimethoxyethane/water (30 mL/10 mL) was added tetrakis(triphenylphosphine)palladium(0) (90 mg, 1.5 mol %) and the reaction mixture was purged with nitrogen and stirred at reflux for 3 h. The reaction was cooled to rt, diluted with water/ethyl acetate (50 mL/50 mL), and the separated aqueous layer was extracted with ethyl acetate. The resulting emulsion was removed by filtration. The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure, and the residue was triturated with toluene for 1 h. The resulting off-white solid was isolated by filtration to give the desired product (1.37 g, 77%) as an off-white solid. MS (EI) for C19H23N3O3: 342 (MH+).
  • 5-(2,3,4,5-Tetrahydrobenzo[f][1,4]oxazepin-7-yl)pyridine-2-amine. To a stirred solution of tert-butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (1.36 g, 3.98 mmol) in 1,4-dioxane (5 mL) was added 4 N hydrogen chloride in 1,4-dioxane (5 mL) and the reaction mixture was stirred at rt overnight. The reaction was concentrated on a rotary evaporator and the residue was triturated with ether. The solid was isolated by filtration. This solid was dissolved in water (5 mL) and made basic with 5 N sodium hydroxide to pH 11-12. The brownish sticky oil that aggregated at the bottom was isolated and the aqueous layer was extracted with 5% methanol in ethyl acetate. The extracts were dried with sodium sulfate and concentrated on a rotary evaporator. The brownish sticky oil was dissolved with a mixture of methanol/ethyl acetate, combined with the isolated organic residue and concentrated under reduced pressure to give a yellow solid. This solid was triturated with dichloromethane (10 mL) for 1 h and a yellow solid was isolated by filtration and dried under high vacuum to give amine the desired product (920 mg, 96%). MS (EI) for C14H15N3O: 242 (MH+).
  • [7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone. To a stirred suspension of 5-(2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)pyridine-2-amine (85 mg, 352 μmol) and triethylamine (54 μL, 387 μmol) in dichloromethane (10 mL) was added 3-fluoro-2-methyl-4-(methylsulfonyl)benzoyl chloride (91 mg, in 3 mL of dichloromethane), prepared as described in Reference Example 1, at 0° C. for 2 h. After stirring for an additional 1 h at rt, the reaction mixture was diluted with water (5 mL) and the separated aqueous layer was extracted with dichloromethane. The combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure to give a light-yellow solid that was purified via silica gel chromatography to give the desired product (113 mg, 70%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.24-8.03 (dd, 1H), 7.79-7.71 (m, 1H), 7.71-7.69 (dd, 0.5H), 7.57-7.57 (d, 0.5H), 7.44-7.40 (m, 1.5H), 7.29-7.19 (dd, 1H), 7.05-7.01 (dd, 1H), 6.64-6.63 (d, 0.5H), 6.54-6.45 (dd, 1H), 6.06 (s, 2H), 4.93-4.31 (m, 2H), 4.31-3.54 (m, 4H), 3.37-3.36 (d, 3H), 2.12-1.77 (d, 3H). MS (EI) C23H22FN3O4S: 456 (MH+).

PAPER

Org. Process Res. Dev., 2015, 19 (7), pp 721–734
DOI: 10.1021/acs.oprd.5b00037

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00037

Abstract Image

The benzoxazepine core is present in several kinase inhibitors, including the mTOR inhibitor 1. The process development for a scalable synthesis of 7-bromobenzoxazepine and the telescoped synthesis of 1 are reported. Compound 1 consists of three chemically rich, distinct fragments: the tetrahydrobenzo[f][1,4]oxazepine core, the aminopyridyl fragment, and the substituted (methylsulfonyl)benzoyl fragment. Routes were developed for the preparation of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid (17) and tert-butyl 7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (2). The processes for the two compounds were scaled up, and over 15 kg of each starting material was prepared in overall yields of 42% and 58%, respectively.

A telescoped sequence beginning with compound 2 afforded 7.5 kg of the elaborated intermediate 5-(2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-2-amine dihydrochloride (6) in 63% yield. Subsequent coupling with benzoic acid 17 gave 7.6 kg of the target compound 1 in 84% yield. The preferred hydrochloride salt was eventually prepared. The overall yield for the synthesis of inhibitor 1 was 21% over eight isolated synthetic steps, and the final salt was obtained with 99.7% HPLC purity.

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone (1)

Compound 1 was observed as a mixture of two rotational isomers in the 1H and 13C NMR spectra.
1H NMR (400 MHz, DMSO-d6): δ 8.24–8.03 (dd, 1H), 7.79–7.71 (m, 1H), 7.71–7.69 (dd, 0.5H), 7.57–7.57 (d, 0.5H), 7.44–7.40 (m, 1.5H), 7.29–7.19 (dd, 1H), 7.05–7.01 (dd, 1H), 6.64–6.63 (d, 0.5H), 6.54–6.45 (dd, 1H), 6.06 (s, 2H), 4.93–4.31 (m, 2H), 4.31–3.54 (m, 4H), 3.37–3.36 (d, 3H), 2.12–1.77 (d, 3H). 13C NMR (100 MHz, DMSO-d6): δ 167.3, 167.2, 166.6, 166.6, 158.9, 158.9, 158.4, 158.4, 157.4, 157.2, 155.9. 155.8, 145.4, 145.1, 145.1, 144.0, 143.9, 135.0, 134.7, 132.9, 132.8, 129.4, 129.2, 128.2, 128.2, 128.1, 128.0, 127.0, 126.9, 126.8, 125.9, 125.6, 125.4, 123.6, 123.5, 123.3, 123.1, 122.8, 122.0, 122.0, 121.9, 121.9, 121.2, 120.7, 107.8, 107.8, 70.9, 70.8, 51.1, 51.1, 47.4, 46.5, 43.5, 43.5, 43.5, 43.4, 11.0, 10.9, 10.7, 10.6. IR (KBr pellet): 1623, 1487, 1457, 1423, 1385, 1314, 1269, 1226, 1193, 1144, 1133, 1054, 1031, 962, 821, 768 cm–1. MS (EI) C23H22FN3O4S: found 456.2 ([M + H]+). High-resolution MS (FAB-MS using glycerol as a matrix) for C23H22FN3O4S: found 456.13943 ([M + H]+), calcd 456.13878.

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone Hydrochloride (1·HCl)

1·HCl as a white solid (7.81 kg, 95%, 99.7% purity by AN-HPLC).
Analyses: OVI: DMF < 100 ppm, DMC < 100 ppm, acetone = 3081 ppm, MTBE < 100 ppm, iPAc < 100 ppm, THF < 100 ppm. Heavy metals: Pd ≤ 0.2 ppm, others < 20 ppm (USP ⟨231⟩). 1H NMR (400 MHz, DMSO-d6), equimolar amounts of two rotamers: δ 8.20–8.40 (br s, 2H), 8.33 (s, 0.5H), 8.31 (d, J = 2.8 Hz, 0.5H), 8.15 (d, J = 2.0 Hz, 0.5H), 7.96 (dd, J = 9.7, 2.0 Hz, 0.5H), 7.70–7.78 (m, 1.5H), 7.55–7.57 (m, 0.5H), 7.51–7.55 (m, 0.5H), 7.28 (d, J = 8.6 Hz, 0.5H), 7.17 (d, J = 3.1 Hz, 0.5H), 7.15 (d, J = 5.1 Hz, 0.5H), 7.05–7.11 (m, 1.5H), 6.83 (d, J = 2.7 Hz, 0.5H), 4.86–4.99 (m, 1H), 4.29–4.56 (m, 1H), 4.10–4.27 (m, 2H), 3.93–4.04 (m, 0.5H), 3.45–3.65 (m, 1.5H), 3.37 (s, 1.5 H), 3.35 (s, 1.5H), 2.12 (d, J = 2.0 Hz, 1.5H), 1.76 (d, J = 2.0 Hz, 1.5H). 13C NMR (100 MHz, DMSO-d6), equimolar amounts of two rotamers: δ 168.1, 167.5, 159.4, 159.2, 159.1, 156.6, 153.9, 153.8, 144.6, 142.9, 142.3, 133.0, 132.7, 130.0, 129.9, 129.7, 129.5, 129.1, 129.0, 128.9, 128.8, 128.5, 127.7, 127.6, 127.5, 127.1, 126.9, 124.4, 124.3, 124.1, 122.7, 122.1, 121.6, 114.4, 71.2, 51.7, 51.3, 47.9, 46.9, 44.3, 44.2, 11.7, 11.4.

REFERENCES

Anand, N.; Benzoxazepines as Inhibitors of PI3K/mTOR and Methods of their Use and Manufacture. U.S. Patent 8,648,066, Feb 11, 2014.

Aay, N.; Benzoxazepines as Inhibitors of PI3K/mTOR and Methods of their Use and Manufacture. U.S. Patent 8,637,499, Jan 28,2014.

US20100305093

US8637499 * May 25, 2010 Jan 28, 2014 Exelixis, Inc. Benzoxazepines as inhibitors of PI3K/mTOR and methods of their use and manufacture
US20120258953 * May 25, 2010 Oct 11, 2012 Exelixis, Inc. Benzoxazepines as Inhibitors of PI3K/mTOR and Methods of Their Use and Manufacture

PROFILE

Sriram Naganathan

Sriram Naganathan

Senior Director

Chemical Development at Dermira, Inc.

Lives San jose caifornia

Sriram NaganathanS.N.: Dermira, Inc., 275 Middlefield Road, Suite 150, Menlo Park, CA 94025.
 
LINKS

https://www.linkedin.com/pub/sriram-naganathan/3/50a/5b6

https://www.facebook.com/sriram.naganathan.5

snaganat@exelixis.com, sriramrevathi@yahoo.com

sriram.naganathan@dermira.com

Summary

Chemical process-development and CMC professional offering 20 years of experience from preclinical development through commercialization of small molecules and peptides.

Hands-on experience in multi-step synthesis, route-scouting, process development, scale-up, tech transfer to CRO/CMO, including manufacture under cGMP and process validation.

Extensive knowledge of CMC regulatory landscape (FDA, EMEA) including preparation of CMC sections of IND, IMPD, NDA and MAA

Experience

Senior Director, Chemical Development

Dermira, Inc.

January 2015 – Present (10 months)Menlo Park, CA

Consultant

Intarcia Therapeutics

December 2014 – January 2015 (2 months)

Senior Director

Exelixis

March 2013 – November 2014 (1 year 9 months)South San Francisco, CA

Exelixis , Inc. 

210 E. Grand Ave

South San Francisco , California 94080
United States
Company Description: Exelixis, Inc. (Exelixis) is developing therapies for cancer and other serious diseases. Through its drug discovery and development activities, the Company is…   more

Director

Exelixis, Inc

July 2008 – February 2013 (4 years 8 months)

Senior Scientist II

Exelixis

August 2004 – January 2008 (3 years 6 months)

Associate Director

CellGate, Inc.

2000 – 2004 (4 years)

Research Scientist

Roche Bioscience

1997 – 2000 (3 years)

Research Scientist

Cultor

1995 – 1997 (2 years)

Research Scientist

Pfizer

1994 – 1997 (3 years)

Research Assistant Professor

University of Pittsburgh

April 1992 – October 1994 (2 years 7 months)

Worked on Vitamin K mechanism in the labs of (Late) Prof Paul Dowd

Education

Vivekananda College (University of Madras), India

Bachelor of Science (B.Sc.), Chemistry

1980 – 1983

(Above) Former Group members join Professor Block at the National ACS Meeting in San Francisco, March 2010: from left, Dr. Shuhai Zhao, Dr. Sherida Johnson, Professor Block, Dr. Sriram Naganathan.

Sriram Naganathan, Ph.D. 1992, snaganat@exelixis.com, sriramrevathi@yahoo.com

snaganathan

As many things change, many things remain constant. One such constant is the frequent reminder that “You can take the boy out of sulfur chemistry but you cannot take sulfur chemistry out of the boy”. At every stage of my professional career organic chemistry of sulfur and sulfur-containing compounds have followed me (or is it the other way around?). Not many can point to the cover of an Angewandte Chemie issue as a synopsis of his/her thesis work – I will be forever grateful for that opportunity received in the Block Group.

As a post-doc in the late Prof. Paul Dowd’s lab at the University of Pittsburgh we used sulfur-containing analogs of vitamin K to probe the mechanism of action. I was then hired at Pfizer Central Research in Groton, CT in the Specialty Chemicals Division to investigate possible decomposition pathways of sulfur-containing high-intensity artificial sweeteners.

At Roche Bioscience (Palo Alto, CA) and Exelixis (South San Francisco, CA – my current job………CHANGED……Dermira) I was involved in process development for the preparation of therapeutic agents, several of them sulfur-containing molecules. Between those two positions I was a Senior Scientist at CellGate (Sunnyvale, CA).

We attempted to exploit the chemistry of sulfur-containing linkers to target the delivery active pharmaceutical agents, using the transport properties of polyarginines. Although I thought I was only training to become a synthetic organic chemist, I did not realize that my passion was really organic reaction mechanisms until I arrived in the Block lab – the two arms of the science are truly inseparable.

I realize after many years that the seed was really sown and nurtured during the many friendly and sometimes-fiery discussions in the lab, and further solidified in my post-doc years. I learned that every “blip-in-the-baseline” cannot to be ignored, and is part of the whole story.

As a process chemist in the pharma industry, I can attribute much of my success to lessons about careful and critical evaluation of primary data and thorough knowledge of reaction mechanisms. I am currently Director, Chemical Development, at Exelixis.NOW DERMIRA.

My primary responsibility involves the manufacture and potential commercialization of our primary product, cabozantinib. It was only natural that I developed a strong interest in the science of cooking and food. I have been pursuing this avenue since moving to Northern California.

I am also an avid gardener, experimenting with growing interesting varieties of chilies, tomatoes and then combining those with all sorts of alliums. It does help that I live close enough to Gilroy, CA, that I can often smell what they are famous for as I walk out of the front door!! I have shared my knowledge in several lectures at the Tech Museum (San Jose, CA) where I was a volunteer exhibit explainer.

My family (my wife Revathi and our two high-school-age daughters Swetha and Sandhya) like to travel and also enjoy the outdoor recreation so abundant in Northern California. We try to take in a new country each year and accomplish personal challenges. After many interesting years in the tech-industry, Revathi is a full-time mom. She is also a fitness instructor at the Y. Swetha and Sandhya are part of the water polo and swim teams at their school.

Swetha is very active in a leadership role for the robotics team, and Sandhya belongs to the quiz team. Revathi and I climbed Half Dome (Yosemite) a few years ago and I just completed a 100-mile bicycle ride around Lake Tahoe.

I remain a highly-opinionated baseball and college basketball fan (favorite teams: in order, Kansas, North Carolina and whoever happens to be playing Missouri and Duke). I am still an avid photographer, although I spend no money on film (I thought I was going to be the last guy on the planet still shooting film!!). I greatly value the many friendships developed during my stay in Albany and keep in touch with many.

In fact, one of my roommates from the SUNY days was instrumental in me getting my present position. Of course, this also means that I have lost touch with several friends during the past decades. If you are reading this and haven’t contacted me in a few years, please do, via e-mail.

We enjoy entertaining guests who drop by – so now you have no excuse not to contact us, especially when you visit the SF Bay Area.

OLD PROFLE……Dr Sriram Naganathan received his Ph.D. from SUNY-Albany where he studied organosulfur chemistry. He is currently an Associate Director at CellGate, Inc. located in Sunnyvale, California. CellGate is involved in the commercialization of novel medicines by utilizing proprietary transporter technology, based on oligomers of arginine, to enhance the therapeutic potential of existing drugs. His responsibilities include process development, scale-up and GMP production of clinical candidates, as well some basic research. He previously held positions at Pfizer Central Research and Roche Bioscience.

Dermira

Thomas G. Wiggans | Founder & Chief Executive Officer……..http://dermira.com/about-us/management-team/

CEO TOM WIGGANS, LEFT AND CMO GENE GAUER, RIGHT

Map of Dermira

Exelixis, Inc.

210 East Grand Avenue
So. San Francisco, CA 94080
(650) 837-7000 phone
(650) 837-8300 fax

Directions to Exelixis, Inc.

101 Northbound from San Francisco Airport:

  • Take 101 North toward San Francisco.
  • Take the Grand Avenue exit, exit 425A, toward So San Francisco.
  • Turn right onto East Grand Ave.
  • 210 East Grand Ave is on your right-hand side.

101 Southbound from San Francisco:

  • Take 101 South.
  • Take the Grand Avenue exit. Turn left at the first light.
  • Immediately turn left at the first light onto Grand Avenue (which will become East Grand Avenue)
  • 210 East Grand Ave is on your right-hand side.

////////////mTOR inhibitor, Exelixis, Inc.,  PI3K,   phosphatidylinositol-3-kinase, XL 388, XL388, IND Filed

%d bloggers like this: