Дапипразол Dapiprazole

Dapiprazole
CAS 72822-12-9
HCL SALT 72822-13-0

5,6,7,8-Tetrahydro-3-(2-(4-(O-tolyl)-1-piperazinyl)ethyl)-S-triazolo(4,3-a)pyridine

Dapiprazole (Rev-Eyes) is an alpha blocker. It is used to reverse mydriasis after eye examination.^[1]
Used in the treatment of iatrogenically induced mydriasis produced by adrenergic (phenylephrine) or parasympatholytic (tropicamide) agents used in certain eye examinations.
Dapiprazole is an alpha-adrenergic blocking agent. It produces miosis by blocking the alpha-adrenergic receptors on the dilator muscle of the iris. Dapiprazole produces no significant action on ciliary muscle contraction and thus, there are no changes in the depth of the anterior chamber of the thickness of the lens. It does not alter the IOP either in normal eyes or in eyes with elevated IOP. The rate of pupillary constriction may be slightly slower in clients with brown irises than in clients with blue or green irises.
Dapiprazole acts through blocking the alpha1-adrenergic receptors in smooth muscle. It produces miosis through an effect on the dilator muscle of the iris and does not have any significant activity on ciliary muscle contraction and, therefore does not induce a significant change in the anterior chamber depth or the thickness of the lens.
Oral LD₅₀ is 1189-2100 mg/kg in mice, rats and rabbits.

Brief background information

Salt	ATC	formula	MM	CASE
–	N05AX S01EX02	C19H27N5	325.46 g / mol	72822-12-9
monogïdroxlorïd	N05AX S01EX02	C19H27N5 · HCl	361.92 g / mol	72822-13-0

Application

• antipsihoticheskoe means
• in the treatment of glaucoma

Classes substance

• Piperazinы
  • 1,2,4-triazolo [4,3-a] piridinы

Synthesis

Синтез a)

Scheme illustration:By cyclization of O-methylvalerolactam (I) with 3-(4-o-tolyl-1-piperazinyl) propionic acid hydrazide (II) in refluxing xylene, followed by a treatment with ethanolic HCl.

FR 2423221; GB 2020269; JP 54157576; NL 7902489; US 4252721

Acylation of (1-methylcyclopropyl)guanidine (IV) with 3-bromo-5-chlorothiophene-2-sulfonyl chloride (III) under Schotten-Baumann conditions afforded the sulfonyl guanidine (V). This was cyclized to the desired thienothiadiazine upon treatment with Cs2CO3 and Cu2O in boiling butanol.


In a different method, (1-methylcyclopropyl)guanidine (I) is acylated by 3-bromo-5-chlorothiophene-2-sulfonyl chloride (II) to produce the sulfonyl guanidine (III). Intramolecular cyclization of (III) in the presence of Cu2O and Cs2CO3 leads to the title thienothiadiazine derivative. Similarly, acylation of guanidine (I) with 3,5-dichlorothiophene-2-sulfonyl chloride (IV) provides sulfonyl guanidine (V), which is then cyclized in the presence of Cu2O and Cs2CO3.


In an alternative method, sulfonylation of N-isopropylguanidine (V) with 2,5-dichlorothiophene-3-sulfonyl chloride (IV) produced the sulfonyl guanidine (VI). This was then cyclized to the title compound by treatment with copper bronze and potassium carbonate in boiling DMF……..WO 0102410

Trade names

country	Tradename	Manufacturer
Germany	Remidrial	winegrower
Italy	Glamidolo	Angelini, 1987
Ukraine	no	no

Formulations

• eyedrops 50 mg / 10 ml (5%) (hydrochloride)

References

• DE 2 915 318 (Angelini; appl. 14.4.1979; I-prior. 18.4.1978).
• US 4 307 095 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
• US 4 307 096 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
• US 4 325 952 (Angelini; 20.4.1982; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
• BE 877 161 (Angelini; appl. 21.6.1979).

References

1. Doughty, Michael J.; Lyle, William M. (May 1992). “A Review of the Clinical Pharmacokinetics of Pilocarpine, Moxisylyte (Thymoxamine), and Dapiprazole in the Reversal of Diagnostic Pupillary Dilation”. Optometry & Vision Science 69 (5).
2. US 4 307 096 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
3.  US 4 325 952 (Angelini; 20.4.1982; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
4. BE 877 161 (Angelini; appl. 21.6.1979).
5. DE 2 915 318 (Angelini; appl. 14.4.1979; I-prior. 18.4.1978).
6. US 4 307 095 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).

Structural formula

UV- Spectrum

Conditions : Concentration – 1 mg / 100 ml
The solvent designation schedule	methanol	water	0.1М HCl	0.1M NaOH
maximum absorption	235 nm	235 nm	234 nm	There decay
	212	179	172	–
e	7650	6450	6200	–

IR – spectrum

Wavelength (μm)
Wave number (cm -1 )

 

References

• UV and IR Spectra. H.-W. Dibbern, R.M. Muller, E. Wirbitzki, 2002 ECV
• NIST/EPA/NIH Mass Spectral Library 2008
• Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman. Academic Press, 2000.
• Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.

Dapiprazole

Systematic (IUPAC) name
3-{2-[4-(2-methylphenyl)piperazin-1-yl]ethyl}-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,5-a]pyridine
Clinical data
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a601043
Pregnancy category	B
Routes of administration	Topical (eye drops)
Legal status
Legal status	℞ (Prescription only)
Pharmacokinetic data
Bioavailability	Negligible when administered topically
Identifiers
CAS Number	72822-12-9
ATC code	S01EX02 (WHO)
PubChem	CID 3033538
IUPHAR/BPS	7155
DrugBank	DB00298
ChemSpider	2298190
UNII	5RNZ8GJO7K
KEGG	D07775
ChEBI	CHEBI:51066
ChEMBL	CHEMBL1201216
Chemical data
Formula	C19H27N5
Molar mass	325.451 g/mol

//////Дапипразол ,  Dapiprazole, AF-2139, Remydrial, Rev-Eyes, Reversil, Glamidolo
n1nc(n2c1CCCC2)CCN4CCN(c3ccccc3C)CC4




BURMA


 

HERE ARE MY 10 REASONS WHY YOU SHOULD PACK YOUR BAGS AND HEAD TO BURMA!

01: The People

For true hospitality, travel to Burma

In my travel experience, out of all the Asians I have met, the Burmese are the kindest, most friendly people who are willing to go above and beyond to make friends with you, help you out and make sure you are having a great time in their country. They always seem to be happy, smiling and keen to practice their English over a glass of tea! They can be quite a shy people as they are extremely polite, kids tend to be the exception to the rule – they will always run up to you to practice their English and unlike the rest of Asia, I was never once hassled by locals for money. The Burmese left a lasting impression on me; I felt that I could truly trust them and I made some incredible connections with locals I met whilst travelling there.

 

02: Insane Temple Ruins

Get lost in some of the biggest temple ruins in the world

When most people think of lost cities they immediately think of Angor Wat in Cambodia or maybe Hampi in India but the ruins of Bagan in central Burma are without a doubt the most stunning, least touristey, ruins I have ever seen. I spent an incredible few days exploring by bike, watching the sun set over Bagan’s temple studded plains and making friends with the local kids out to practice their English. For the true adventurer, you can head even deeper into the country’s largely unexplored regions and visit the stunning temple ruins at Mrauk Au, you will probably have them all to yourself.

03: Real Exploring

Discover the Asia of 100 years ago

Burma is an absolutely massive country and there are many hidden gems in this astounding country which only the locals will know about. It is extremely easy to get off the beaten track and to have temples, ruins, mountains and caves all to yourself. When backpacking in Burma, I felt like I had stepped back 100 years in to the past, I felt like a proper explorer. The people who I met in remote communities in the Shan highlands had often not seen another westerner for months or even years, this is prime exploring territory.  Whilst exploring the south of the country I came across a huge field of painted Buddha statues, some were cracked and covered by jungle, others looked freshly painted. Who built, painted and maintained them? I have no idea. This is why I love Burma. 

04: Trekking

Take to the hills and meet awesome people

Trekking in Burma is a relatively new activity but already tour agencies are springing up to cater for adventourous backpackers. Most backpackers opt for a two day trek around the stilt villages of Inle Lake but for a real experience; head deep into the Shan highlands or South to Hp-Pan. Here you can summit jungle clad limestone peaks, many of which are topped by small monastries, and soak in some spectacular views. Trekking in Burma is a really amazing experience; I met colourful freshwater crabs, hiked through mist draped forests and shared tea with novice monks who spoke no English but always seemed happy to see me.

Stilt villages, Inle

Paddy fields

Novice monk watching the mist

Tofu enthusiasm

05: Monks

Spiritual-esque discussions galore

Speaking of Monks, it’s pretty hard to travel in Burma without meeting a few! I had some amazing discussions with monks I met in temples, on buses, in the street or even whilst riding my bicycle. I was told by a monk that 1% of Burma’s entire population are monks and they certainly seem to be everywhere. Whilst trekking I met a shy monk working on repairing a temple wall, we chatted for a while and I spent an hour helping him, he offered me tea and allowed me to take his photograph. I came away with a much richer understanding of what Buddhism is all about. The monks are a friendly bunch and would often ask me all kinds of questions about life outside Burma, spirituality and even football!

 


 

06: Food

 “Really? The food’s OK?” I hear you ask…

The food is better than OK, Burmese cuisine is some of the best in Asia. Sure, there may not be many Burmese restaurants outside of Burma but that’s largely because the country has been shut off from the rest of the world for so long. The food is an eclectic mix of Thai, Chinese and Indian cuisine and basically includes all the best bits from Thai, Chinese and Indian dishes. Check these tasty, one of a kind, dishes out:

– Gyin Thohk – tasty ginger salad with sesame seeds.
– Fruit Shakes – Keep an eye out for creamy avocado and banana shakes around Inle Lake
– Kat Kyi Hnyat – The Burmese answer to Pad Thai, a gorgeous coastal dish of rice noodles with seafood, meats, raw bean sprouts and fried eggs.
– Danbauk – A tasty Indian inspired curry served with mango pickle, fresh mint and green chili.
– Shan Tofu – Do not miss this awesome home-made tofu from the Shan highlands.

07: Cheap Beer!

Beer for 50 cents?!

I have made it a personal mission to sample as many local beers throughout the world as I possibly can… so far, Myanmar Beer is without a doubt my favourite brand. For just 50 cents, you can have a cool, refreshing, tap drawn beer in a iced glass. For five bucks, you can get well and truly merry. Mandalay Beer makes a tasty alternative if you get sick of Myanmar Beer but I can guarantee you won’t.

08: Stunning Islands & Beaches

Burma has a hidden paradise of unexplored beaches and islands

Most Backpackers are not yet aware that Burma has some of the world’s most beautiful beaches and islands. Until recently, these palm-fringed, white sand playgrounds were off limits unless you had a super-yacht handy but this is changing fast and every week more and more restrictions are being lifted. Now is the perfect time to travel to Burma and hunt for your dream island; think coral blue waters, coconut cocktails and perfect sandy beaches, the opportunities are endless. There are over 800 islands in Burma’s Mergui archipelago which are currently empty, making this the perfect opportunity to head out on a kayak or boat and discover paradise in the ocean.

09: Caves

Discover cavernous underground temples filled with Buddha images

When travelling, I’m always looking for adventurous ways to keep myself busy, whether it’s living in a cave with a Bedouin or mountain biking through the jungles of Laos. In Burma, there is a ton of activities for the adventurous traveller but one of the best has got to be exploring some of the huge caves which pockmark the country. Many of these are not covered by any guidebook, it’s simply a case of asking around and seeing if there are any cool caves nearby. One of the biggest which I visited, in the South of the country, was filled with huge Buddha images and statues as well as some beautiful rock formations. I walked through it for over an hour, it must have been about three kilometres long, before I emerged on the other side to find a hidden lake framed by a backdrop of limestone mountains; to this day it is still one of the most beautiful things I have discovered whilst backpacking.

Cave temples

Cave tunnels

The view from inside a huge cave

Inside the caves of Hp-Pan

10: It’s changing fast

Now is the time to go!

Burma is well and truly back on the Backpacker map and in 2014 it has become THE place to go. I was lucky enough to first visit in 2012 and I met perhaps a dozen backpackers in my entire time there. These days, more and more backpackers are tagging Burma on to the classic Thailand – Laos – Vietnam – Cambodia route, and rightly so! However, as the country continues to open up and as investment and travelers continue to pour in it is only a matter of time before some of Burma’s most enchanting attractions become diluted. Luckily, the country is so big that there is plenty of room and plenty of wild places left for backpackers to explore. Do not hesitate; visit this incredible land now, meet the wonderful people, have a beer or three and explore till your heart’s content.

The Golden Rock

Friendly locals

A jungle crab I met trekking

Laying golden leaf on the Buddha

Epic temples

The Buddha and 500 Sanghas

Local kid in Hp-Pan

Inle Lake stilt villages

 
…AND NOW? PACK YOUR BACKPACK, BOOK YOUR FLIGHT AND GET OUT THERE!!
Need some more information? Check out this travel guide I wrote based on my travels in Burma.