Midaflur: Difference between revisions

Midaflur
Clinical data
ATC code	None;
Identifiers
	IUPAC name 2,2,5,5-Tetrakis(trifluoromethyl)-2,5-dihydro-1H-imidazol-4-amine;
CAS Number	23757-42-8;
PubChem CID	32068;
ChemSpider	29737;
UNII	840CTL676L;
KEGG	D05027;
ChEMBL	ChEMBL2104707;
CompTox Dashboard (EPA)	DTXSID50178425;
Chemical and physical data
Formula	C7H3F12N3
Molar mass	357.103 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1(=NC(NC1(C(F)(F)F)C(F)(F)F)(C(F)(F)F)C(F)(F)F)N;
	InChI InChI=1S/C7H3F12N3/c8-4(9,10)2(5(11,12)13)1(20)21-3(22-2,6(14,15)16)7(17,18)19/h22H,(H2,20,21); Key:KYWMWUUMCDZISK-UHFFFAOYSA-N;

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Revision as of 09:13, 9 December 2022

Midaflur (INN; EXP 338) is an extremely stable 3-imidazoline derivative with central skeletal muscle relaxant and sedative properties in humans^[1] and other species of mammals, exhibiting consistently high oral bioavailability and a long duration of action. While its pharmacodynamics remain poorly understood, midaflur resembles meprobamate and pentobarbital in terms of observed effects while being considerably more potent.^[2]

Synthesis

Addition of sodium cyanide to hexafluoroacetone imine [1645-75-6] (1) gives a tetrahedral intermediate (2). The anionic charge on the primary nitrogen then goes on to react with a second molecule of HFAI to form a dimer (3); addition of a third HFAI now results in a trimer through a process of cyclization into a 3-imidazoline after quenching of the delocalized ionic charge on 4. Hydrolytic cleavage of hexafluoroisopropylamine on (5') in strong acid completes the Midaflur synthesis stratagem (6).

References

^ Levine IM, Jossmann PB, Friend DG, DeAngelis V (1967). "Effect of 5-imino-2,2,4,4-tetrakis (trifluoromethyl) imidazolidine (EXP 338) on spasticity: A quantitative evaluation". Clinical Pharmacology and Therapeutics. 9 (4): 448–55. doi:10.1002/cpt196894448. PMID 4871898. S2CID 39263140.
^ Clark R, Lynes TE, Price WA, Smith DH, Woodward JK, Marvel JP, Vernier VG (April 1971). "The pharmacology and toxicology of midaflur". Toxicology and Applied Pharmacology. 18 (4): 917–43. doi:10.1016/0041-008x(71)90239-0. PMID 5570243.
^ Middleton, William J.; Krespan, Carl G. (1970). "Fluorinated aminoimidazolines. Synthesis and determination of tautomeric structure". The Journal of Organic Chemistry. 35 (5): 1480–1485. doi:10.1021/jo00830a048.
^ William J Middleton, US3567831 (1971 to EI Du Pont de Nemours and Co).
^ William J Middleton, US3459766 (1969 to EI Du Pont de Nemours and Co).
^ William J Middleton, US3410866 (1968 to EI Du Pont de Nemours and Co).
^ David M Gale, US3536704 (1970 to EI Du Pont de Nemours and Co).
^ William J Middleton, US3342864 (1967 to EI Du Pont de Nemours and Co).

[1] Levine IM, Jossmann PB, Friend DG, DeAngelis V (1967). "Effect of 5-imino-2,2,4,4-tetrakis (trifluoromethyl) imidazolidine (EXP 338) on spasticity: A quantitative evaluation". Clinical Pharmacology and Therapeutics. 9 (4): 448–55. doi:10.1002/cpt196894448. PMID 4871898. S2CID 39263140.

[2] Clark R, Lynes TE, Price WA, Smith DH, Woodward JK, Marvel JP, Vernier VG (April 1971). "The pharmacology and toxicology of midaflur". Toxicology and Applied Pharmacology. 18 (4): 917–43. doi:10.1016/0041-008x(71)90239-0. PMID 5570243.

[3] Middleton, William J.; Krespan, Carl G. (1970). "Fluorinated aminoimidazolines. Synthesis and determination of tautomeric structure". The Journal of Organic Chemistry. 35 (5): 1480–1485. doi:10.1021/jo00830a048.

[4] William J Middleton, US3567831 (1971 to EI Du Pont de Nemours and Co).

[5] William J Middleton, US3459766 (1969 to EI Du Pont de Nemours and Co).

[6] William J Middleton, US3410866 (1968 to EI Du Pont de Nemours and Co).

[7] David M Gale, US3536704 (1970 to EI Du Pont de Nemours and Co).

[8] William J Middleton, US3342864 (1967 to EI Du Pont de Nemours and Co).

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@@ Line 27: / Line 27: @@
 '''Midaflur''' ([[International Nonproprietary Name|INN]]; '''EXP 338''') is an extremely stable [[imidazoline|3-imidazoline]] derivative with central skeletal muscle relaxant and [[sedative]] properties in humans<ref>{{cite journal | vauthors = Levine IM, Jossmann PB, Friend DG, DeAngelis V | title = Effect of 5-imino-2,2,4,4-tetrakis (trifluoromethyl) imidazolidine (EXP 338) on spasticity: A quantitative evaluation | journal = Clinical Pharmacology and Therapeutics | volume = 9 | issue = 4 | pages = 448–55 | date = 1967 | pmid = 4871898 | doi = 10.1002/cpt196894448 | s2cid = 39263140 }}</ref> and other species of mammals, exhibiting consistently high oral bioavailability and a long duration of action. While its [[pharmacodynamics]] remain poorly understood, midaflur resembles [[meprobamate]] and [[pentobarbital]] in terms of observed effects while being considerably more potent.<ref>{{cite journal | vauthors = Clark R, Lynes TE, Price WA, Smith DH, Woodward JK, Marvel JP, Vernier VG | title = The pharmacology and toxicology of midaflur | journal = Toxicology and Applied Pharmacology | volume = 18 | issue = 4 | pages = 917–43 | date = April 1971 | pmid = 5570243 | doi = 10.1016/0041-008x(71)90239-0 }}</ref>
+==Synthesis==
+[[File:Midaflur synthesis.svg|thumb|center|500px|Synthesis:<ref>Middleton, William J.; Krespan, Carl G. (1970). "Fluorinated aminoimidazolines. Synthesis and determination of tautomeric structure". The Journal of Organic Chemistry. 35 (5): 1480–1485. doi:10.1021/jo00830a048.</ref> Patents:<ref>William J Middleton, US3567831 (1971 to EI Du Pont de Nemours and Co).</ref><ref>William J Middleton, US3459766 (1969 to EI Du Pont de Nemours and Co).</ref><ref>William J Middleton, US3410866 (1968 to EI Du Pont de Nemours and Co).</ref><ref>David M Gale, US3536704 (1970 to EI Du Pont de Nemours and Co).</ref> Precursor:<ref>William J Middleton, US3342864 (1967 to EI Du Pont de Nemours and Co).</ref>]]
+Addition of sodium cyanide to hexafluoroacetone imine [1645-75-6] ('''1''') gives a tetrahedral intermediate ('''2'''). The anionic charge on the primary nitrogen then goes on to react with a second molecule of HFAI to form a dimer ('''3'''); addition of a third HFAI now results in a trimer through a process of cyclization into a 3-imidazoline after quenching of the delocalized ionic charge on '''4'''. Hydrolytic cleavage of hexafluoroisopropylamine on ('''5'''') in strong acid completes the Midaflur synthesis stratagem ('''6''').
 == See also ==
 * [[Propofol]]