PDE4 Inhibitors

Development of a Practical Process for the Synthesis of PDE4 Inhibitors

Rogelio P. Frutos^*, Thomas G. Tampone, Jason A. Mulder, Sonia Rodriguez, Nathan K. Yee, Bing-Shiou Yang, and Chris H. Senanayake

Chemical Development US, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877-0368, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00104

Publication Date (Web): April 28, 2016

Copyright © 2016 American Chemical Society

*rogelio.frutos@boehringer-ingelheim.com.

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Vis island  krka park, croatia

Vis

Island in the Adriatic Sea

Vis is a small Croatian island in the Adriatic Sea. The farthest inhabited island off the Croatian mainland, Vis had a population of 3,460 in 2011 and has an area of 90.26 square kilometres. Wikipedia

Vis island & krka park, croatia - swimming in secret bays and waterfalls

After Dubrovnik, Sara and I took a long-haul bus whose passengers were 50% rowdy, hungover Australians and 50%  totally asleep Chinese, up the Dalmatian Coast to our new home base in Split. Our few days based in Split were built roughly around two dreams: Sara wanted to swim at the base of a waterfall, and I wanted to see Vis Island.

Fifty kuna (eight bucks) will get you on a Jadrolinija ferry to Hvar, Brač, Korčula, or Šolta -- all lush paradises with perfect golden beaches, fresh seafood, colorful port towns and unspoiled nature galore.

Pulling away from Split...

... and into Vis.

Vis is the furthest of the Dalmatian islands from the coast, and its isolation, coupled with its history (until the late 1980s) as a Yugoslav military base, means the island has avoided over-development (or, really, much development at all) and preserved its abundant natural beauty.

Arriving on the ferry, I wanted to take off on foot to find Stiniva Beach, had nothing but a very rough idea of what direction to go in, and was completely unaware that we'd be walking along the side of the only road, a tiny winding wisp of pavement which locals took at six hundred kilometeres per hour in their rickety old Fiats.

Sara put her foot down and demanded we figure out how far away Stiniva was from the port (quite far) and whether we could get there on foot (no). Off to hail a taxi.

Me, to taxi driver: "We'd like to go to Stiniva Beach."
Taxi driver: *looks down at my breasts* *looks up at my face* "Yes."

Our charming driver winged around the sharp turns, careening over terrifying cliffs and through idyllic grape fields, while blasting at top volume, on repeat, LMFAO's 'Champagne Showers'. It was a jarring experience.

Arriving at the little sign for Stiniva Beach, we had a 20 minute descent about 85 degrees straight down a cliff face.

With every step, the beach comes a little more into view -- we're headed to that yellow roof near the bottom.

 All worth it, the second your feet touch sand -- er, rocks.

We ripped off our clothes and jumped in.

And did a little exploring. There were folks snorkeling, solo climbing, and cliff jumping, and we did a bit of everything (though our "solo climbing" efforts were much less majestic than the actual rock climber, and consisted mostly of stepping extremely carefully around urchins).

Sara bravely takes a leap!

There's a little shack on the beach. When we walked over to ask if they had food, the merry surfer dues running the joint said, "Sure, we got a cook! What do you want?"

We shelled out a couple bucks for cold beers to go.

Before we knew it, it was time to make the ascent back up the rock face to meet our favorite cabbie.

Goodbyes are so hard.

 Our cabbie/best friend pointed out all the best vineyards on the island (Vis makes some of Croatia's best wine) and invited us to a houseparty his bro was throwing, but we'd had our fill of "Champagne Showers" for the day. Enough "Champagne Showers" for a damn lifetime.

We were plenty early for our ferry, so wandered around the town at the port a bit, soaking every last bit in.

Last glance of Vis as the ferry pulls out from the port.

Pulling into Split at sunset.

If you can hack it, make it to Vis Island, and to Stiniva Beach. It's the most spectacular place I've ever swam in, and in the past year, I've racked up a startling amount of good secret swimming holes. Don't be deterred by the steep, perilous climb. Get there early or stay late to avoid rush hour of tourist boats cramming into the bay. And bring a couple bucks to buy a cold beer.

Back in Split, we got a huge take out pizza a piece and a cold bottle of bubbly and ate on the port, laughing for hours, having funny conversations with strangers who passed by. It was a warm night and everyone was happy and in a good mood. This is my kind of nightlife.

Another day, we set out to check off a big item on Sara's bucket list: swimming at the base of a waterfall.

We took a bus into Split, then a bus to Krka National Park, and then a ferry to get to the waterfalls.

We chose Krka over the more popular but remarkably beautiful Plitvice just to cut out four hours on a bus. It was a beautiful day, perfect for a cool swim.

The park is built around the 73km Krka River, which carved a path through limestone hills forming a 200m deep canyon. Calcium carbonate buildup causes billions of plants growing on top of one another to form a barrier that produces the spectacular 800m waterfalls.

Sara, dream list to-do crossed off, blissed out.

They're not hanging out in a perfectly straight line for fun (we're not in Switzerland. ZING) -- the falls are roped off, and risk takers are confronted with a speed boat manned by vicious tanned teenage lifeguards who guide you back behind the ropes.

Sara was in heaven, and me.... this is not my scene. No words can express how massively crowded this place was -- but maybe the photo below can. People had spread out blankets on the fields next to the river, and people were essentially shoulder to shoulder, blanket edges overlapping.

I like my space and my solitude when hanging out in nature, and Krka at 2pm on a Monday just before August was.... the opposite of that.

Sara and I had been warned of the crowds (Lonely Planet Croatia: "insanely busy"), and vowed to arrive early. We left our apartment in the boondocks at 6am, and, after a bus into the city, a bus to Skradin, and then humongous lines for park entrance tickets and then the same humongous line to catch the ferry to the waterfalls, we got there at 1pm. Pro tip: wake up well before sunrise, splurge for a taxi, get there early. It'd be worth it.

Unless you're a person like Sara, of course, an endless well of zen positivity.

There is a path that cuts around and through the park (about an hour long), which we hiked for a respite from the crowds.

Selfie with the 800m Skradinski Buk -- the waterfalls -- behind us.

Next week, one last post from Croatia: downtown Split.

All photos taken by either Sara or me -- we can't remember whose is whose anymore!








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CDRI 830

CDRI 830

CDRI S006-830

S 006-830

CAS 1550975-42-2

N-[2-[4-[(4-methoxyphenyl)-thiophen-2-ylmethyl]phenoxy]ethyl]-N-propan-2-ylpropan-2-amine

Molecular Formula:	C26H33NO2S
Molecular Weight:	423.61072 g/mol

CDRI-830 of thiophene containing trisubstituted methane (TRSM) class was identified as an anti-tubercular lead with MIC value of 1.33 mg/L against Mycobacterium tuberculosis H37Rv strain, non-toxicity against Vero C-1008 cell line (selectivity index >10), ex vivo efficacy (in mouse and human macrophages) equivalent to first line TB drugs, lung CFU count (2.2×107) comparable to pyrazinamide (1.9×107) and ethambutol (1.27×107). CDRI-830 has exhibited potent bactericidal activity against single and multi-drug resistant clinical isolates of M. tuberculosis. Furthermore, CDRI-830 has demonstrated good pharmacokinetic properties with fast intestinal absorption, peak plasma concentration one hour post oral dose, optimum elimination half-life (9-13 h), plasma protein binding (~60%), favorable bioavailability (45-50%) and mean residence time (18-20 h).

CDRI S006-830 is a potent triethylamine containing thiophene antitubercular compound of the Central Drug Research Institute, India. The present study aimed to conduct comprehensive metabolic investigations of CDRI S006-830 to corroborate its preclinical investigations. Preliminary metabolic investigations were performed to assess the metabolic stability, enzyme kinetics, reaction phenotyping, and metabolite identification of CDRI S006-830 in rat, rabbit, dog, and human liver microsomes using liquid chromatography with mass spectrometry. The observed in vitro t_1/2 and Cl_int values were 9.9 ± 1.29, 4.5 ± 0.52, 4.5 ± 0.86, 17 ± 5.21 min and 69.60 ± 8.37, 152.0 ± 17.26, 152.34 ± 27.63, 33.62 ± 21.04 μL/min/mg in rat, rabbit, dog and human liver microsomes respectively. These observations suggested that CDRI S006-830 rapidly metabolized in the presence of NADPH in liver microsomes of rat, rabbit and dog while moderately metabolized in human liver microsomes. It was observed that CDRI S006-830 exhibited monophasic Michaelis–Menten kinetics. The metabolism of CDRI S006-830 was primarily mediated by CYP3A4 and was deduced by CYP reaction phenotyping with known potent inhibitors. CYP3A4 involvement was also confirmed by cDNA-expressed recombinant human isozyme activity with different CYPs. Four major phase-I metabolites of S006-830, (M-1 to M-4) were detected in rat, rabbit, dog (except M4) and human liver microsomes........http://onlinelibrary.wiley.com/doi/10.1002/dta.1802/abstract?systemMessage=Wiley+Online+Library+will+be+unavailable+on+Saturday+14th+May+11%3A00-14%3A00+BST+%2F+06%3A00-09%3A00+EDT+%2F+18%3A00-21%3A00+SGT+for+essential+maintenance.Apologies+for+the+inconvenience.

NMR

13C NMR

SYNTHESIS

 

Gautam Panda



Associate Professor AcSIR ( Academy of Scientific and Innovative Research, New Delhi, India) Principal Scientist and Group Leader Medicinal and Process Chemistry Division CSIR-CDRI ( Central Drug Research Institute ) Sector-10, Jankipuram Extension, Sitapur Road, Lucknow-226031 Phone (Office) : 0522-2772450, 2772550, Ext. 4661, 4662 Phone (Res.) : 0522-2746635 Fax : 0522-2771941 Email : gautam.panda@gmail.com, gautam_panda@cdri.res.inWebpage: http://www.cdriindia.org/gautampanda.htm

PATENT

Indian Pat. Appl. (2012), IN 2010DE00685

Abstract:
The invention relates to Thiophene containing Trisubstituted Methanes (TRSMs) and a process for the preparation thereof. The invention particularly relates to a process for the preparation of substituted secondary and tertiary amino alkoxy diary! thiophenyl methanes and their use as potential antimycobacterial agents. Novel diaryl thiophenyl methanes of formula I have been prepared. The present invention provides novel diaryl thiophenyl methanes substituted with a secondary or tertiary amino alkoxy group and a process for the preparation of the said compounds of general formula I comprising general formula la and lb useful in antimycobacterial activity wherein R1 is selected from an aryl group or thophene moiety wherein the aryl group is selected from a group consisting of substituted phenyl groups such as methoxy phenyl, thiomethoxy phenyl, phenyl, p-chlorophenyl, p-fluorophenyl; R2 is selected from a group consisting of aminoalkoxyl, alkyl/dialkyl aminoalkoxy, cyclic alkyl aminoalkoxy. R3 is selected from a group consisting of H, lower alkyl, lower alkoxy group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-amyl, n-hexyl, 2-ethyl butyl; R4 is selected from a group consisting of H,OH,methyl.

The invention relates to thiophene containing Trisubstituted Methanes (TRSMs) and a process for the preparation thereof. The invention particularly relates to a process for the preparation of substituted secondary and tertiary amino alkoxy diaryl thiophenyl methanes and their use as potential antimycobacterial agents. Novel diaryl thiophenyl methanes of formula I have been prepared.
The present invention provides novel diaryl thiophenyl methanes substituted with a secondary or tertiary amino alkoxy group and a process for the preparation of the said compounds of general formula I comprising formula la and lb useful in antimycobacterial activity wherein R1 is selected from an aryl group or thophene moiety wherein the aryl group is selected from a group consisting of substituted phenyl groups such as methoxy phenyl, thiomethoxy phenyl, phenyl, p-chlorophenyl, p-fluorophenyl; R2 is selected from a group consisting of aminoalkoxyl, alkyl/dialkyl aminoalkoxy, cyclic alkyl aminoalkoxy. R3 is selected from a group consisting of H, lower alkyl, lower alkoxy group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-amyl, n-hexyl, 2-ethyl butyl ; R4 is selected from a group consisting of H,OH,methyl etc.
(Formula Removed)
Background of the Invention
Tuberculosis is a growing international health concern; it is the leading infectious cause of death in the world today (Dolin, P.J. et al Bull. WHO 1994, 72, 213; Daffe, M. et al Adv. Microb. Physiol 1998, 39, 131). It is estimated that worldwide 100 million people are infected annually.

Approximately ten million develop the disease, with five million of these progressing to the infectious stage and ultimately three million dying. Even though improved methods of prevention, detection, diagnosis and modern treatment have greatly reduced the number of people getting infected and dying from it, the emergence of multi-drug-resistant (MDR) strains and the global human immunodeficiency virus (HIV) augments the risk of developing TB many fold. Resistance has been described for all first-line drugs (isoniazid, rifampin, pyrazinamide, ethambutol and streptomycin) and for several second-line and newer drugs (ethionamide, fluoroquinolones, macrolides, nitroimidazopyrans). Because MDR strains are the result of cumulative mutations, growth of Mycobacterium tuberculosis (MT) can successfully be controlled in the host by concomitant treatment with more than one drug. This has resulted in the development of new agents (Panda, G. et al Indian Journal of Chemistry, 2009, 48B, 1121-1127; Parai, M. K. et al Bioorganic & Medicinal Chemistry Letters, 2008, 18, 289-292) for the preparation of Disseminated Mycobacterium avium complex (DMAC) infection as well as combinations of both new and standard agents for its treatment. The search for more effective agents against Mycobacterium tuberculosis (MT) and Mycobacterium avium complex (MAC) is ongoing in an attempt to enhance survival and reduce morbidity, as proven by the high number of publications (Jing-Ping Lu et al J. Med. Chem., 2010, 53, 3, 1329-1337; Liqiang Chen et al J. Med. Chem., 2010, 53 (12), 4768-4778; Jiyoung A et al J. Med. Chem., 2009, 52 (17), 5485-5495; Maria-Teresa Gutierrez-Lugo et al J. Med. Chem., 2008, 51 (9), 2606-2612; Li Liu et al J. Med. Chem., 2010, 53 (7), 2882-2891 and references cited therein) and patents of new antituberculous drugs recently published. Preclinical data, such as in vitro measures of drug activity and pharmacokinetics, are used in the design of new treatment regimens. Assessment of pharmacodynamic activity from standard in vitro minimum inhibitory concentrations (MICs) alone is insufficient to predict in vivo potency. Achievable serum and tissue concentrations as well as pharmacokinetic characteristics must be considered.
Because of this, there is an urgent need for anti-TB drugs with improved properties such as enhanced activity against MDR strains, reduced toxicity, shortened duration of therapy, rapid mycobactericidal mechanism of action and the ability to penetrate host cells and exert anti-mycobacterial effects in the intracellular environment.
Following is the description of thiophene containing trisubstituted methanes having antimycobacterial activity.

 

PAPER

European Journal of Medicinal Chemistry (2015), 95, 357-368

http://www.sciencedirect.com/science/article/pii/S0223523415002032

Thiophene containing trisubstituted methanes [TRSMs] as identified lead against Mycobacterium tuberculosis

• Priyanka Singh^a,
• Sudipta Kumar Manna^a,
• Amit Kumar Jana^a,
• Tiash Saha^a,
• Pankaj Mishra^a,
• Saurav Bera^a,
• Maloy Kumar Parai^a,
• Srinivas Lavanya Kumar M^a,
• Sankalan Mondal^a,
• Priyanka Trivedi^b,
• Vinita Chaturvedi^b,
• Shyam Singh^b,
• Sudhir Sinha^b, , , ,
• Gautam Panda^a, , ,

• ^a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, B.S. 10/1, Jankipuram Extension, Sitapur Road, Lucknow-226031, UP, India
• ^b Biochemistry Division, CSIR-Central Drug Research Institute, B.S. 10/1, Jankipuram Extension, Sitapur Road, Lucknow-226031, UP, India

Triarylmethanes (TRAMs) and thiophene containing trisubstituted methanes (TRSMs) have been reported by us, having potential against Mycobacterium tuberculosis andMycobacterium fortuitum strains, respectively. Further, extension through synthesis and biological evaluation of novel TRSMs resulted into an identified lead 36 (S006-830) [(diisopropyl-(2-{4-[(4-methoxy-phenyl)- thiophen-2-yl-methyl]-phenoxy}-ethyl)-amine)] with MIC: 1.33 mg/L, non-toxic against Vero C-1008 cell line with selectivity index >10,ex vivo efficacy equivalent to first line TB drugs-isoniazid (INH), rifampicin (RFM) and pyrazinamide (PZA) in the mouse and human macrophages, and lung CFU count of 2.2 × 10⁷ (approximately 15 fold lesser than untreated mice, 31 × 10⁷) with efficacies comparable to ethambutol (EMB) (1.27 × 10⁷) and PZA (1.9 × 10⁷). Further, S006-830 also showed potent bactericidal activity against multi-drug resistant and single-drug resistant clinical isolates of M. tuberculosis

.

PAPER

Synthetic Communications (2014), 44(23), 3408-3413

Abstract

The triarylmethane antituberculosis drug CDRI-830 is synthesized. The triarylmethane derivative 4 is prepared from ether 6 by a rearrangement process. The total synthesis of the drug CDRI-830 is achieved in a good overall yield of 35% from a simple thiophene derivative 8.

Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry Volume 44, Issue 23, 2014

Total Synthesis of an Experimental Antitubercular DrugDOI:

10.1080/00397911.2014.942745

Uma Reddy Pailla^ab, Veera Reddy Arava^a* & L. K. Ravindranath^b

pages 3408-3413

http://www.tandfonline.com/doi/abs/10.1080/00397911.2014.942745

REFERENCES

http://www.ingentaconnect.com/content/ben/cpa/2015/00000011/00000001/art00008?crawler=true

S006-830 against H37RV, single, multi-drug resistant M. tuberculosis; CFU in the lungs with S006-830, EMB, PZA (European Journal of Medicinal Chemistry 2015, 95, 357-368, J Antimicrob Chemother. 2012; 67(5):1188-97, Bioorg Med Chem Lett, 2008, 18, 289-292)

Panda, G., Parai, M.K., Das, S.K., Shagufta, Sinha,M., Chaturvedi, V., Srivastava, A.K., Manju,

Y.S., Gaikwad, A.N., and Sinha, S.: Effect of substituents on diarylmethanes for antitubercular activity.

European Journal of Medicinal Chemistry;2007,42, 410-419

Drug Testing and Analysis (2016), 8(2), 180-188.

Current Pharmaceutical Analysis (2015), 11(1), 35-42.

Drug Testing and Analysis (2015), 7(8), 721-726

Indian Pat. Appl. (2012), IN 2010DE00685

1.  DiaryloxyMethanoPhenanthrenes: A New Class of Antituberculosis Agents, G. Panda,Shagufta, Jitendra Kumar Mishra, Vinita Chaturvedi, Anil K. Srivastava, Manju, RanjanaSrivastava and Brahm S. Srivastava,        1178DEL2004 Filing date 24/06/04

2. Thiophene containing Trisubstituted Methanes (TRSMs) as antitubercular agents, Gautam Panda, Maloy Kumar Parai, Priyanka Singh, Sudhir Sinha, Vinita Chaturvedi, Anil Gaikwad, PCT in process (685/DEL/2010) dt 20-2-2010

/////////S 006-830, CDRI 830, 1550975-42-2

c1c(ccc(c1)OC)C(c2ccc(cc2)OCCN(C(C)C)C(C)C)c3sccc3

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 Ajanta Caves, Aurangabad, maharashtra, india



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Ajanta Caves  

4.4434 Google reviews

Cave

The Ajanta Caves in Aurangabad district of Maharashtra state of India are about 30 rock-cut Buddhist cave monuments which date from the 2nd century BCE to about 480 or 650 CE. Wikipedia

Address: Maharashtra 431117

Hours:

Open today · 8AM–5PM

UNESCO World Heritage Site inscription: 1983

 

 


 

 


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