Author Topic: 3-methylfentanyl  (Read 5857 times)

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HumbleStudent

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3-methylfentanyl
« on: July 12, 2004, 05:38:00 PM »
I have been trying to gather information on 3-methylfentanyl and I have some questions that I cannot find the answers to.

1. What is the therapeutic index of 3-methyfentanyl?
2. I read on some german website that 3-methyfentanyl is highly hypnotic and toxic.  Is this true?

... and no, I have no interest in synthesizing anything.  Just so you know.

Thank you.

descent

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on mice and men
« Reply #1 on: July 12, 2004, 09:55:00 PM »
According to the first publication on the subject the Thepeutic Index (LD50/ED50) of methylfentanyl is 1662; of fentanyl - 255; morphine - 75.6; pethidine - 4.89. It can be read in J. Med. Chem. 1974, v. 17, No10, the exact page is 1050. By a strange coincidence I have the paper wright now on my desk. But this impressive and highly optimistic safety margin was obtained from rat data which, sincerely said, are a little more than useless when speeking about humans. All opiates, including fentanyls, are very different for humans (they feel them like ... like opiates) and for rodents (they feel them rather like stimilants). All fentanyl derivatives have a specific effect on humans, especially when introduced i.v. - transitory paralysis of breathing. It's not the usual opiate respiraty depression; with fentanyls it's brief but in many cases fatal. It is occuring only during I.V. administartion and you will guess that it is not the usual method for drug administration on lab rats but unfortunately is typical for humans. I have not used fentanyls myself but I have friends who have used simple fentanyl and they will be very sceptic on their high safety margin. At least in humans. Be very carefull when interpreting lab rat data!

Rhodium

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3-Methylfentanyl has a high Therapeutic Index
« Reply #2 on: July 12, 2004, 10:11:00 PM »
According to Casy & Parfitt's book "Opioid Analgesics", this article will contain all the data you want, in detail.

N-4-Substituted 1-(2-arylethyl)-4-piperidinyl-N-phenylpropanamides, a novel series of extremely potent analgesics with unusually high safety margin.
Van Bever WF, Niemegeers CJ, Schellekens KH, Janssen PA., Arzneimittelforschung. 1976;26(8):1548-51.

Medline (PMID=12771)



The intravenous analgesic activity and toxicity of a novel series of N-[4-substituted 1-(2-arylethyl)-4-piperidinyl]-N-phenylpropanamides was studied in rats. Onset, potency and duration of analgesic action were assessed in the tail withdrawal test and compared with the activity of fentanyl, (+)-cis-3-methylfentanyl (R 26 800), morphine, and pethidine. All compounds studied were found to be extremely potent analgesics characterized by an unusually high safety margin. Methyl 4-[N-(1-oxopropyl)-N-phenyl-amino]-1-(2-phenylethyl)-4-piperidinecarboxylate (R 31 833; lowest ED50 = 0.00032 mg/kg) is the most potent compound (10 031 times morphine). cis-Methyl 3-methyl-4-[N-(1-oxopropyl)-N-phenylamino]-1-(2-phenylethyl)-4-piperidine carboxylate (R 32 792) is the longest acting compound (more than 8 h at 4 times the lowest ED50) and N-[4-(1-oxopropyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide (R 33 352) is the shortest acting compound (0.74 h at 4 times the lowest ED50) of the 4-substituted fentanyl derivatives. N-[4-(Methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide (R 30 730) was selected for further investigation. R 30 730 has a rapid onset of action and is 4521 times more potent than morphine at the time of peak effect; it has a relatively short duration of action comparable to that of fentanyl and its safety margin (LD50/lowest ED50 = 25 211) is unusually high.
____ ___ __ _

Sufentanil, a very potent and extremely safe intravenous morphine-like compound in mice, rats and dogs.
Niemegeers CJ, Schellekens KH, Van Bever WF, Janssen PA., Arzneimittelforschung. 1976;26(8):1551-6.

Medline (PMID=12772)



Sufentanil (R 30 730), N-[4-methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide, is a chemically novel, highly potent and extremely safe intravenous morphine-like agent in laboratory animals. In mice R 30 730 i.v. is 2304 times more potent than morphine (hot plate ED50's: 0.0028 and 6.45 mg/kg, respectively). The i.v. safety margin of R 30 730 in mice is 1 : 6 679 (LD50 = 18.7 mg/kg). Under the same experimental conditions the safety margin of pethidine is 1 : 7.97, of morphine 1 : 34.9 and of fentanyl 1 : 454. In rats R 30 730 i.v. is 4521 times more potent than morphine (tail withdrawal test ED50's: 0.00071 and 3.21 mg/kg, respectively). The i.v. safety margin of R 30 730 in rats is 1 : 25 211 (LD50 : 17.9 mg/kg). Under the latter experimental conditions the safety margin of pethidine is 1 : 4.80, of morphine 1 : 69.5 and of fentanyl 1 : 277. In dogs R 30 730 i.v. is 2429 times more potent than morphine (apomorphine antagonism test ED50's: 0.00028 and 0.68 mg/kg, respectively). The i.v. safety margin in dogs is approximately 1 : 50 000, the LD50 being +/- 14.0 mg/kg. All morphine-like effects of R 30 730 are immediately antagonized by nalorphine. These pharmacological findings are relevant in connection to the increasing interest for use of morphinomimetics in anesthesia.


____ ___ __ _

Studies on synthesis and relationship between analgesic activity and receptor affinity for 3-methyl fentanyl derivatives.
Jin WQ, Xu H, Zhu YC, Fang SN, Xia XL, Huang ZM, Ge BL, Chi ZQ., Sci Sin. 1981 May;24(5):710-20.

Medline (PMID=6264594)



    In the present paper, the synthesis and analgesic activity (mice, i.p. hot plate test) of the derivatives of 3-methyl fentanyl are briefly described. Compound 7302, cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropionamide (cis: 3-methyl/4-N-phenylpropionamide) is found to be the most potent analgesic agent in this series synthesized by our laboratory (ED50 = 0.0022 mg/kg). The analgesic activity of 7302 is 28 times more potent than that of fentanyl and 6300 times more than that of morphine. The partition coefficients of 10 compounds in the series are determined by high performance liquid chromatography (HPLC) and their log p values are about 3. There are no regular relationships between the analgesic activity and partition coefficients. Study on the specific binding of 8 out of the above 10 compounds to crude synaptic plasma membrane (P2-fraction) of mouse brain demonstrates that there is an excellent statistical linear correlation (r = 0.998) between the analgesic potency and the specific binding affinity. The result shows that the analgesic potency of the derivatives of this series is mainly dependent on binding affinity for opiate receptor.


HumbleStudent

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I know this is redundant, but thank you both...
« Reply #3 on: July 12, 2004, 10:50:00 PM »

HumbleStudent

  • Guest
Spillage
« Reply #4 on: July 16, 2004, 03:51:00 AM »
As some of you know, I'm writing a book(fiction) and it deals with conspiracies, drugs etc.

I just need confirmation on a few ideas... or is the idea too far fetched?

Although I've read this in posts (After using TFSE), I just need confirmation...

What if someone accidentally poured say 5 ml of liquid with a narcotizing dose of 3-methylfentanyl or something equally potent (carfentanil) on his or her skin, would the person become high etc. (ie. get the effects of the substance)?  My uneducated guess would be yes, he would as the amount needed is so small that it would be absorbed almost instantaneously.

Your help will be appreciated.  Thank you.

HumbleStudent

  • Guest
synthesis of N-phenethyl-3-methyl-piperidone-4
« Reply #5 on: July 20, 2004, 05:54:00 AM »

HumbleStudent

  • Guest
N-phenethyl-3-methyl-piperidone-4
« Reply #6 on: July 20, 2004, 06:28:00 PM »

HumbleStudent

  • Guest
C'mon bees, help me out.
« Reply #7 on: July 21, 2004, 03:17:00 AM »

HumbleStudent

  • Guest
UTFSE???
« Reply #8 on: July 30, 2004, 04:27:00 AM »
Umm, I did, If you noticed, I even mentioned that in the posts.  I cannot find any info on synethising N-phenethyl-3-methyl-peiperidone-4 from piperidone-4(monohydrochloride).  I asked whether one solution I thought of was correct... and all I get is UTFSE?  Believe me, I did.

What the fuck are you guys smoking???  Rate this as insignificant too.  Thats all you fucked up high and mighty sanctimoneous moderators do anyway... Instead of giving a helping hand, you keep saying use the fucking search engine...  I didn't ask, give me the recipe of such and such, or make xyz for me, I asked for pointers or documents that can show me the way.

I used to think of you guys as being chemists who are open to questions and helping newbies not up to your standards to better understand this subject, but you guys are not.  You gys act like highschool kids with their own cliques where outsiders are harshly treated.  Some of you really act like immature pricks.

What are you going to do now, ban me because you consider me an annoyance in your perfect little totalitarian world?  I expect as much now.  (I'll withhold the name calling the moderator deserves.) 

Again, this is the question In asked, maybe my FSE skills aren't up to par.
"Could someone tell me or point me to any doc that explains how one would get N-phenethyl-3-methyl-piperidone-4 from 4-piperidone ?"

I checked again, and the FSE doesn't come up with any doc which contains anywhere near this answer.

>:(  >:(  >:(  >:(  >:(  >:(  >:(

armageddon

  • Guest
hm, let's search a bit...
« Reply #9 on: July 30, 2004, 05:05:00 AM »
What I found:

Post 438010

(pHarmacist: "Substituted N-Phenylpropanamides", Novel Discourse)


Post 60132 (missing)

(Rhodium: "N-phenylethyl-4-piperidones via acrylates", Chemistry Discourse)


Dunno NOTHING about opioid/fentanyl chemistry, but TFSE turned up LOADS of even whole threads about the topic when searching for "3-methylfentannyl"...

I SERIOUSLY doubt that all those texts are only about its pharmacology!!!!

Greetz A


Rhodium

  • Guest
Synthesis of N-phenethyl-3-methyl-4-piperidone
« Reply #10 on: July 30, 2004, 06:40:00 AM »
This is what I understand:
For N-phenethyl-piperidone-4, 4-piperidone, acetonitrile and phenethylbromide is used... right?


Yes, see the reaction diagram in

https://www.thevespiary.org/rhodium/Rhodium/chemistry/fentanyl.html



4-Piperidone is alkylated with phenethylbromide in acetonitrile solution to give N-phenethyl-4-piperidone (abbreviated NPP in the diagram).

So would one be able to synthesize N-phenethyl-3-methyl-piperidone-4 by using methylethylketone instead of acetonitrile?

Your question does not make any sense - acetonitrile just acts as a solvent in this reaction. By what kind of reasoning did you arrive at this proposal?


Again, this is the question In asked, maybe my FSE skills aren't up to par.
"Could someone tell me or point me to any doc that explains how one would get N-phenethyl-3-methyl-piperidone-4 from 4-piperidone ?"
I checked again, and the FSE doesn't come up with any doc which contains this answer.


Of course not - there is no such thing! If you compare their structures you see that you would need to attach a methyl group next to the carbonyl to arrive at your target compound, and that chemical transformation only looks good on paper...

If you research general preparations of 4-piperidones (something which would be very reasonable to do if you are contemplating this kind of chemistry) you will soon discover that the available routes are rather few, the most important being the following:

Michael Reaction:

Post 60132 (missing)

(Rhodium: "N-phenylethyl-4-piperidones via acrylates", Chemistry Discourse)

Mannich Reaction:

Post 496728

(Megatherium: "Discussing the Mannich reaction", Serious Chemistry)

Post 481189

(josef_k: "You can use this method to use the the mannich", Newbee Forum)

via Allylsilanes:

Post 411081

(thallium: "Total Synthesis of Fentanyl", Novel Discourse)

Post 411082

(thallium: "RESULTS AND DISCUSSION Our synthetic approach...", Novel Discourse)



HumbleStudent

  • Guest
Thanks, see...
« Reply #11 on: July 30, 2004, 07:27:00 AM »
"Of course not - there is no such thing! If you compare their structures you see that you would need to attach a methyl group next to the carbonyl to arrive at your target compound, and that chemical transformation only looks good on paper..."

See, a simple answer with an excellent explanation which made me realize that I misunderstood a lot of the docs I've read and clearly shows my lack of real world knowledge.  Now I understand a lot more and know what stuff to reread.  Thank you.

P.S. - I have gone through all the links the 2 of you have provided before I posted my question, but being naive, I thought the piperidone-4 route was possible and was asking about that.  Now Rhodium has answered the question elegantly.

Bozakium

  • Guest
3-methylfentanyl
« Reply #12 on: July 30, 2004, 07:14:00 PM »
Bee careful in your dreams. I seem to remember reading somewhere that the potency of these 3-substituted fentanys being more potent by weight than LSD. Just a dab will DO ya. Just remember, do spelled backward is od.

demorol

  • Guest
3-alkylfentanyl analogues
« Reply #13 on: October 11, 2004, 02:00:00 PM »
The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analogues
M. D. Ivanovic, I. V. Micovic, S. Vuckovic, M. Prostran, Z. Todovic, V. D. Kiricojevic, J. B. Djordjevic and LJ. Dosen-Micovic
J. Serb. Chem. Soc. 69(7), 511–526 (2004)

Abstract

A general, five step method for the synthesis of 3-alkylfentanyl analogues (i.e., cis and trans 3-alkyl-4-anilidopiperidines 6.16.6) has been developed. The starting N-phenethyl-4-piperidone 1 was first converted into the cyclohexylimine derivative 2, alpha-deprotonated with butyllithium and the resulting imine anion efficiently monoalkylated with primary and secondary alkyl halides. After mild acid hydrolysis, the obtained 3-alkyl-4-piperidones 3.13.6 were isolated in good yields (79–85 %), then condensed with aniline to form imines 4.14.6. Subsequent reduction of the imines (LiAlH4/THF) yielded cis/trans mixtures of 3-alkyl-4-anilinopiperidines 5.15.6. Quantitative separation of the diastereoisomers by column chromatography of Al2O3 gave pure cis 5.15.6 (29–51 % yield) and trans 5.15.6 (19–27 % yield), with the cis/trans ratio in the range 7/3–6/4. The synthesis was concluded by N-acylation of the purified 5.15.6, with propionyl chloride, to afford cis and trans 3-alkyl-4-anilidopiperidines 6.16.6 (~95 % yield, as monooxalate salts). No enatioseparation was attempted at any stage. The relative cis/trans stereochemistry was provisionally assigned from the 1H-NMR spectra. Of the twelve synthesized 3-alkylfentanyls, ten compounds (two known and eight novel derivatives, all as the monooxalate salts) were preliminarily tested as analgesics in rats, comparing the potency to fentanyl. Except for the known (±)-cis-3-Me fentanyl 6.1cis, (8 × fentanyl), and the novel (±)-cis-3-Et fentanyl 6.2cis, (1.5 × fentanyl), all of the others were less active than fentanyl or inactive. Some tentative conclusions on the structure-activity relationship (SAR) in this series of derivatives have been made.


Full text available for free at:

http://www.shd.org.yu/htdocs/shd/Vol69/No7.html#1


Offline Chemxer

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Re: 3-methylfentanyl
« Reply #14 on: February 10, 2016, 06:28:52 PM »
There is a very valuable paper on the synthesis and pharmacology of many fentanyl analogs, including 3-alkyl called, "Fentanyl-related compounds and derivatives: Current status and future prospects for pharmaceutical applications" by Ruben S. Vardanyan and Victor J. Hruby.
This may prove useful for understanding SAR relationships of fentanyl. It has given me some ideas for which I'm tempted to contact a chinese custom synth lab, as they are fairly far off the traditional fentanyl structure.

Offline java

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Re: 3-methylfentanyl
« Reply #15 on: February 12, 2016, 02:29:33 AM »
Requested by Chemxer

Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications
Ruben S Vardanyan* and Victor J Hruby
Future Med Chem.
2014 Mar; 6(4): 385–412.
doi:  10.4155/fmc.13.215



Abstract
Fentanyl and its analogs have been mainstays for the treatment of severe to moderate pain for many years. In this review, we outline the structural and corresponding synthetic strategies that have been used to understand the structure–biological activity relationship in fentanyl-related compounds and derivatives and their biological activity profiles. We discuss how changes in the scaffold structure can change biological and pharmacological activities. Finally, recent efforts to design and synthesize novel multivalent ligands that act as mu and delta opioid receptors and NK-1 receptors are discussed.
« Last Edit: February 12, 2016, 02:34:03 AM by java »
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