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Bromadol

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Not to be confused with bromidol, bromadoline, or Bromadiolone.
Bromadol
Bromadol.png
Systematic (IUPAC) name
4-(4-Bromophenyl)-4-(dimethylamino)-1-(2-phenylethyl)cyclohexanol
Clinical data
Legal status
?
Identifiers
CAS number 77239-98-6 YesY
70895-01-1 (HCl)
ATC code None
PubChem CID 9887338
ChemSpider 26001358 YesY
Chemical data
Formula C22H28BrNO 
Mol. mass 402.37 g/mol
Physical data
Melt. point 208–210 °C (406–410 °F)
 YesY (what is this?)  (verify)

Bromadol (systematic name 4-(4-bromophenyl)-4-(dimethylamino)-1-(2-phenylethyl)cyclohexanol, BDPC) is a potent narcotic analgesic with a distinctive chemical structure. It was developed by Daniel Lednicer at Upjohn in the 1970s.1 Initial studies showed that it was around 10,000 times the strength of oxymorphone2 in animal models although later studies assigned a value of x504 morphine for the more active trans-isomer.3 To date it is unknown if this drug has been used by humans, however, it was seized along with three kilograms of acetylfentanyl in an April 25, 2013 police action in Montreal, Canada. Despite taking precautions, at least two officers became intoxicated due to handling the drugs.4

Opioid pharmacology

Bromadol has never been studied in humans, but would be expected to produce effects similar to those of other potent opioid agonists, including strong analgesia, sedation, euphoria, constipation, itching and respiratory depression which could be harmful or fatal. Tolerance and dependence would be expected to develop rapidly based on the potency of the drug, as it is of a similar strength to sufentanil and so would most likely cause pronounced tachyphylaxis following repeated dosing, as is seen with the potent fentanyl analogs.

Structure-activity relationships

Several related analogs such as the p-methyl and ring-unsubstituted compounds have also been investigated.5 Bromadol is the lead compound in this series that attracted so much interest in it initially. A large number of analogs have been prepared,67 and the SAR is very well established. Lednicer constructed Dreiding models to show that the model of bromadol will give an exact overlay on a model of fentanyl.

Ar X flick pinch
meperidine.HCl 22 29
morphine sulfate 1.5 1.6
pentazocine lactate 7 6
p-tolyl O 1 4
p-tolyl OCH2CH2O 3 2
p-Cl O 8 9
p-Cl OCH2CH2O 4 3
p-Br O 4 5
p-Br OCH2CH2O 3 3
m-phenol O 45 45
m-phenol OCH2CH2O >100 >100
X R isomer flick pinch % yield
p-Cl CH2CH2CH=CH2 trans 0.018 0.018 21
p-Cl Bn trans 0.0056 0.0056 28
p-Cl CH2CH2Ph trans 0.0014 0.0014 19
p-Br CH2CH2Ph trans 0.0001 0.0001 13
m-OH CH2CH2Ph trans 0.005 0.006 19
m-OH Bn trans 0.18 0.18 23

Synthesis

1,4-Cyclohexanedione,8

Bromadol can be synthesized from 4-hydroxycyclohexanone.9

  • The oxo group is ketalized with the appropriate glycol and the remaining 3°OH is oxidized with CrO3/DCM to the corresponding ketone. For example, if ethyleneglycol is used then the product is called 1,4-dioxaspiro[4.5]decan-8-one.
  • Above product is then reacted with dimethylamine in the presence of KCN, c.f. phencyclidine, carfentanil, etc. (Strecker-type α-aminonitrile).
  • Product above step could be treated with Grignard reagent from m-bromophenol tetrahydropyranyl ether.
doi:10.1021/jm00135a019

A procedure exists to prepare the monoketal of cyclohexanedione.1011

4-Amino-4-arylcyclohexanones

Synthesis starts by double Michael reaction of acrylate on arylacetonitriles. Following cyclization, decarboxylation, ketalization, and saponification, the geminally substituted acid is rearranged to the isocyanate by means of (PhO)2PON3 (diphenylphosphonic azide). Note, that in the Curtius rearrangement chemical reaction, the acyl azide is rearranged to an isocyanate. Carboxylic acid can be converted to azide as part of a two-step procedure (c.f. tranylcypromine), or see Schmidt reaction where -CO2H reacted with HN3 directly.

Isocyanates were then converted to the 4-Amino-4-arylcyclohexanones. First he reduced it with LAH to methylamines, then 2° amines were methylated with formaldehyde/SBH. If instead the isocyanate is reacted with water, then it is hydrolyzed to the corresponding 1° amine (Lossen rearrangement).

Bromadol Precursor Synthesis

Analgesic activity is very sensitive to the nature and position of the substitutent on the aromatic ring. The most potent compounds in this series (p-CH3, p-Br) showed 50% the potency of morphine. Deletion of the ring oxygen abolishes activity.

Patents

See also

References

  1. ^ U.S. Patent 4,366,172 - 4-Amino-cyclohexanols, their pharmaceutical compositions and methods of use
  2. ^ Lednicer, D.; Vonvoigtlander, P. F. (1979). "4-(p-Bromophenyl)-4-(dimethylamino)-1-phenethylcyclohexanol, an extremely potent representative of a new analgesic series". Journal of Medicinal Chemistry 22 (10): 1157–1158. doi:10.1021/jm00196a001. PMID 513062.  
  3. ^ Liu, Z. H.; Jin, W. Q.; Dai, Q. Y.; Chen, X. J.; Zhang, H. P.; Chi, Z. Q. (2003). "Opioid activity of C8813, a novel and potent opioid analgesic". Life Sciences 73 (2): 233–241. doi:10.1016/S0024-3205(03)00263-7. PMID 12738037.  
  4. ^ "Extremely potent painkiller hits Montreal black market". CBC News. May 13, 2013. 
  5. ^ Report 1985, 21 pages, from Foersvarets Forskningsanstalt, Umea, Sweden. (Report in Swedish)
  6. ^ Lednicer, D.; Vonvoigtlander, P. F.; Emmert, D. E. (1981). "4-amino-4-arylcyclohexanones and their derivatives: a novel class of analgesics. 2. Modification of the carbonyl function". Journal of Medicinal Chemistry 24 (4): 404–408. doi:10.1021/jm00136a010. PMID 7265128.  
  7. ^ Lednicer, D.; Von Voigtlander, P. F.; Emmert, D. E. (1981). "4-aryl-4-aminocyclohexanones and their derivatives, a novel class of analgesics. 3. M-Hydroxyphenyl derivates". Journal of Medicinal Chemistry 24 (3): 341–346. doi:10.1021/jm00135a019. PMID 7265120.  
  8. ^ "1,4-Cyclohexanedione". Organic Syntheses 45: 25. 1965. doi:10.15227/orgsyn.045.0025. 
  9. ^ Radlick, P.; Crawford, H. T. (1972). "Simple synthesis of 4-hydroxycyclohexanone". The Journal of Organic Chemistry 37 (10): 1669. doi:10.1021/jo00975a046. 
  10. ^ Haslanger, M.; Lawton, R. G. (1974). "A Facile Preparation of the Ethylene Glycol Mono-Ketal of Cyclohexane-1, 4-Dione". Synthetic Communications 4 (3): 155. doi:10.1080/00397917408062065. 
  11. ^ Hsi, R. S. P.; Kurtz, R. R.; Moon, M. W. (1987). "Synthesis of tritium and deuterium labeled 8-N-n-butyl-N-methylamino-8-(3-hydroxyphenyl)-1,4-dioxaspiro[4,5]decane hydrochloride". Journal of Labelled Compounds and Radiopharmaceuticals 24 (11): 1381. doi:10.1002/jlcr.2580241115. 



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