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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March 2017

Scheduling medicines and poisons

17 May 2017

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2.1 N-(alkylamino) cyclohexylbenzamides (opioids)

2. Joint meeting of the Advisory Committee on Chemicals and Medicines Scheduling (ACCS/ACMS #15)

2.1 N-(alkylamino) cyclohexylbenzamides (opioids)

Referred scheduling proposal

An application was initiated by the delegate to seek advice from the Joint Advisory Committees on Chemicals and Medicines Scheduling (ACCS-ACMS) to include a new class entry for N-(alkylamino)cyclohexylbenzamides in Schedule 9, except when separately specified in these schedules.

Current scheduling status and relevant scheduling history

3,4-Dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide, U-47700, is not currently scheduled and there is currently no class entry for N-(alkylamino)cyclohexylbenzamides.

A scheduling history is not available for U-47700 or for N-(alkylamino)cyclohexylbenzamides as a class since these have not been previously considered for scheduling.

The related structural isomer 3,4-dichloro-N-{[1-(dimethylamino)cyclohexyl]methyl}benzamide, *AH 7921, is currently listed in Schedule 9 under the entry:

Schedule 9

3,4-DICHLORO-N-{[1-(DIMETHYLAMINO)CYCLOHEXYL]METHYLBENZAMIDE *(AH-7921).

It was placed in Schedule 9 in June 2014 following reported deaths in Sweden and increased use of the substance in Australia through monitoring of Australian internet forums, as well as claims that the substance has no legitimate therapeutic use. The final scheduling decision for AH-7921 was published on the TGA website in May 2014 at: Scheduling delegate's final decisions: May 2014.

Scheduling application

Delegate-initiated application.

The delegate's proposed amendment to the Poisons Standard is as follows:

Schedule 9 - Proposed New Entry

N-(ALKYLAMINO)CYCLOHEXYLBENZAMIDES except when separately specified in these Schedules.

Index - Proposed New Entries

3,4-DICHLORO-N-[(1R,2R)-2-(DIMETHYLAMINO)CYCLOHEXYL]-N-METHYLBENZAMIDE *(U-47700)
cross reference: N-(ALKYLAMINO)CYCLOBENZAMIDES

Schedule 9

N-(ALKYLAMINO)CYCLOBENZAMIDES
cross reference: 3,4-DICHLORO-N-{[1-(DIMETHYLAMINO)CYCLOHEXYL]METHYL}BENZAMIDE *(AH 7921)

Schedule 9

The delegate's reasons for the scheduling proposal are:

  • Safety concerns have been raised that N-(alkylamino)cyclohexylbenzamides (such as 3,4-dichloro-N-[(1R,2R)-2-(dimethylamino)cyclohexyl]-N-methylbenzamide, U-47700) are being abused overseas, and pose a public health risk, requiring restrictions on their use. U-47700 is a novel synthetic opioid that was recently placed in Schedule 1 by the US Drug Enforcement Administration (DEA), following association with morbidity (46 confirmed deaths in the USA) and abuse parallels with that of heroin, prescription opioids and other novel opioids. US enforcement agencies have found these substances in counterfeit tablets mimicking pharmaceutical opioids.
  • These substances are opiates and appear to have no legitimate therapeutic use.
  • The opioid analgesic substance 3,4-dichloro-N-{[1-(dimethylamino)cyclohexyl]methylbenzamide (AH-7921), a structural isomer of U-47700, is already included in Schedule 9.
Australian regulatory information

U-47700 does not have legitimate medical use in Australia and is not in any registered medicines. No legitimate industrial uses have been identified.

AH-7921 does not have legitimate medical use in Australia.

NICNAS could not locate any AICS-listed chemicals meeting this description. The National Chemical Inventories program includes one chemical, 116174-38-0 (benzamide, N-(cyanomethyl)-N-[(1R,2R)-2-[[(methylsulfonyl)oxy]methyl]cyclohexyl]-), with presumed industrial use, but this was not considered to fall within the relevant class description N-(alkylamino)cyclohexylbenzamides. This has been pre-registered under REACH, but it is not on any chemicals inventory.

International regulations

The US DEA and FDA in 2016 placed U-47700 and its isomers, esters, ethers, salts and salts of isomers, esters and ethers, in Schedule 1, effective from 14 November 2016, following confirmed deaths and inclusion of the powder form in counterfeit pharmaceuticals.

In the U.K. U-47700 is controlled under the Psychoactive Substances Act 2016. In Sweden, following sale in 2016 as a designer drug, U-47700 was made illegal in January 2016. Finland labelled U-47700 a controlled substance in September 2015.

U-47700 was reviewed at the World Health Organization (WHO) Expert Committee on Drug Dependence summit in November 2016 - see UNODC critical review report for U-47700 attached.

U-47700 is not controlled under the 1961, 1971 or 1988 United Nation Conventions.

No information is available on related scheduling in New Zealand.

Substance summary

N-(alkylamino)cyclohexylbenzamides are synthetic opioid analgesics, and include 3,4-dichloro-N-[(1R,2R)-2-(dimethylamino)cyclohexyl]-N-methylbenzamide, U-47700, which is unscheduled, and 3,4-dichloro-N-{[1-(dimethylamino)cyclohexyl]methyl}benzamide, AH-7921, which has been in Schedule 9 since 2014. U-47700 is a structural isomer of AH-7921. In both isomers, the benzamide moiety is dichlorinated at the 3 and 4 ring positions and the aminocyclohexane moiety is N,N-dimethylated.

Figure 2.1A: Chemical structure of U-47700 (free base, trans stereochemistry)

Figure 2.1A: Chemical structure of U-47700 (free base, trans stereochemistry)

Figure 2.1B: Chemical structure of AH-7921 (free base, trans stereochemistry)

Figure 2.1B: Chemical structure of AH-7921 (free base, trans stereochemistry)

Table 2.1: General information
U-47700 AH-7921
CAS No. 82657-23-6 (free base, trans); 121348-98-9 (form not specified) 55154-30-8 (free base); 41804-96-0 (hydrochloride salt)
IUPAC name 3,4-dichloro-N-[(1R,2R)-2-(dimethylamino)cyclohexyl]-N-methylbenzamide 3,4-dichloro-N-{[1-(dimethylamino)cyclohexyl]methyl}benzamide
Synonyms U4, fake morphine, pinky, pink[33] 1-(3,4-dichlorobenzamidomethyl)cyclohexyldimethylamine; doxylam
Molecular formula C16H22Cl2N2O C16H22Cl2N2O
Molecular weight 329.3 g/mol 329.3 g/mol
Scheduling status unscheduled Schedule 9
U-47700

U-47700 is a white powder. Chemical properties of U-47700 include: melting point: 97-98.5°C, boiling point 465°C, solubility is sparingly soluble in water (0.49 g/L), at pH 10.36 very soluble (527 g/L). U-47700 contains 2 chiral centres at the bonds to the 2 nitrogens off the ring resulting in 4 isomers; cis and trans each have 2 enantiomers [cis: are (1R,2R), and (1S,2S); trans are (1R,2S) and (1S,2R)]. The absolute configuration of the µ-agonist enantiomer was originally reported as R,R.

Identified risks of U-47700 include developing substance abuse, overdose, and death similar to that of other opioid analgesics (e.g., fentanyl, morphine, etc.). Since 2015, abuse of U-47700 has been reported as the single substance and in combination with other substances, including heroin, fentanyl, and furanyl fentanyl. The population likely to abuse U-47700 appears to overlap with the populations abusing prescription opioid analgesics, other "designer opioids", and heroin, as evidenced by drug use history documented in U-47700 fatal overdose cases.

U-47700 became the lead compound of several selective kappa-opioid receptor ligands such as U-50488, U-51754 (with a single methylene spacer difference) and U-69,593, with similar structures[34]. It has no medical use[35]. Research use has been reported[36].

Media reports that U-47700 can be taken by injection, inhalation, and oral administration. An internet search indicates that U-47700 is available via the internet for up to $US35/gram[37].

The DEA placement of U-47700 in Schedule 1 raises concerns that, since this is obtained through illicit sources, the identity, purity, and quantity are uncertain and inconsistent, thus posing significant adverse health risks to the end user.

The DEA placement of U-47700 in Schedule 1 states:

  • Evidence suggests that the pattern of abuse of U-47700 parallels that of heroin, prescription opioid analgesics, and other novel opioids. Seizures of U-47700 have been encountered in powder form and in counterfeit tablets that mimic pharmaceutical opioids.
  • U-47700 is available over the Internet and is marketed as a "research chemical".
  • U-47700 exhibits pharmacological profiles similar to that of morphine and other µ-opioid receptor agonists. Cases of intoxication are reported in the literature with morbidity and mortality associated with U-47700 use. The toxic effects of U-47700 in humans are demonstrated by overdoses and overdose fatalities associated with this substance, as reported in the scientific literature.

Adverse reactions reported in humans are described in the WHO UNODC report. This report details misuse, abuse and dependence by humans and indicates significant abuse potential and that there are no marketing authorizations as a medicinal product for U-47700 and it has no legitimate industrial use. Seizures have been reported relating to use in Europe and the USA with reports of opiate-like adverse effects and associated fatalities.

AH-7921

AH-7921 is an opioid analgesic substance selective for the µ-opioid receptor, having around 80% the potency of morphine when administered orally. It was discovered in the 1970's by a team at Allan and Hanburys Ltd, a British pharmaceutical manufacturer. A trivial name, doxylam, has been proposed for this compound, but it has never been sold commercially for medical use. In 2013, AH-7921 was discovered to have been used as an active ingredient in "synthetic cannabis" products in Japan.

The free base form of AH-7921 is a solid; its melting point is not known. The hydrochloride salt, also a solid, has been documented to have a melting point of 215-216°C (see ECMDDA Europol Joint Report, attached). This refers to a 1974 study by Harper et al., which details that the LD50 of AH-7921 is higher than 10 mg/kg upon intravenous administration in the rat. No studies were identified examining toxicity in humans and insufficient information was available to determine its acute toxicity.

Pre-meeting public submissions

One (1) submission was received. The submission indicated that there were no known non-medical uses of the substances. Further information may be required to assess the impact of the regulation proposal.

The public submission will be made available on the TGA website.

Summary of ACCS-ACMS advice to the delegate

The committee advised that a new Schedule 9 entry be created for N-(alkylamino)cyclohexylbenzamides.

Schedule 9 - Proposed New Entries

N-(ALKYLAMINO)CYCLOHEXYLBENZAMIDES except when separately specified in these Schedules.

N-(ALKYLAMINO)CYCLOHEXYLMETHYLENEBENZAMIDES except when separately specified in these Schedules.

3,4-DICHLORO-N-[(1R,2R)-2-(DIMETHYLAMINO)CYCLOHEXYL]-N-METHYLBENZAMIDE (U-47700).

Index - Proposed New Entries

N-(ALKYLAMINO)CYCLOHEXYLBENZAMIDES
cross reference: 3,4-DICHLORO-N-[(1R,2R)-2-(DIMETHYLAMINO)CYCLOHEXYL]-N-METHYLBENZAMIDE *(U-47700)

Schedule 9

N-(ALKYLAMINO)CYCLOHEXYLMETHYLENEBENZAMIDES except when separately specified in these Schedules.
cross reference: 3,4-DICHLORO-N-{[1-(DIMETHYLAMINO)CYCLOHEXYL]METHYL}BENZAMIDE *(AH 7921)

Schedule 9

3,4-DICHLORO-N-[(1R,2R)-2-(DIMETHYLAMINO)CYCLOHEXYL]-N-METHYLBENZAMIDE (U-47700)
cross reference: N-(ALKYLAMINO)CYCLOHEXYLBENZAMIDES

Schedule 9

The committee also recommended an implementation date of 1 October 2017.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the extent of use; (c) the toxicity of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice comprised the following:

  • There is a significant public health risk similar to other opioid analgesics, such as morphine and fentanyl, including abuse potential, dependence, toxicity and overdose. Furthermore, N-(alkylamino)cyclohexylbenzamides poses a risk of overdose.
  • There are no registered products, and there are no benefits from therapeutic use for N-(alkylamino)cyclohexylbenzamides.
  • Toxicity reports for N-(alkylamino)cyclohexylbenzamides are similar to other opioid analgesics such as fentanyl and morphine, which includes fatal overdose cases. There is also a significant potential for abuse similar to heroin and other illicit prescription and novel opioids.
  • There have been reports of illicit use. N-(alkylamino)cyclohexylbenzamides are also likely to have significant abuse liability given pharmacological profile. Although no animal studies are available to confirm this, the WHO report describes 'user reports' of tolerance and craving.
  • Since N-(alkylamino)cyclohexylbenzamides are obtained through illicit sources, the identity, purity, and quantity are uncertain, are inconsistent and therefore pose significant risks to the end-user.
  • There are no known medical or industrial uses.
  • Significant mortality has been noted internationally. They may be sold as heroin, or mixed with heroin, and this contributes to overdoses.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal
  • ACCS-ACMS advice
  • Public submissions received
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information
Delegate's interim decision

The delegate's interim decision is to create new Schedule 9 entries for N,N-dialkylaminocyclohexyl alkyl benzamides and N,N-dialkylaminocyclohexylmethyl alkyl benzamides. The proposed Schedule entry is as follows:

Schedule 9 - New Entries

N,N-DIALKYLAMINOCYCLOHEXYL ALKYL BENZAMIDES except when separately specified in these Schedules.

N,N-DIALKYLAMINOCYCLOHEXYLMETHYL ALKYL BENZAMIDES except when separately specified in these Schedules.

3,4-DICHLORO-N-[(1R,2R)-2-(DIMETHYLAMINO)CYCLOHEXYL]-N-METHYLBENZAMIDE (U-47700).

Index - Proposed New Entries

N,N-DIALKYLAMINOCYCLOHEXYL ALKYL BENZAMIDES
cross reference: 3,4-DICHLORO-N-[(1R,2R)-2-(DIMETHYLAMINO)CYCLOHEXYL]-N-METHYLBENZAMIDE *(U-47700)

Schedule 9

N,N-DIALKYLAMINOCYCLOHEXYLMETHYL ALKYL BENZAMIDES
cross reference: 3,4-DICHLORO-N-{[1-(DIMETHYLAMINO)CYCLOHEXYL]METHYL}BENZAMIDE *(AH 7921)

Schedule 9

3,4-DICHLORO-N-[(1R,2R)-2-(DIMETHYLAMINO)CYCLOHEXYL]-N-METHYLBENZAMIDE (U-47700)
cross reference: N,N-DIALKYLAMINOCYCLOHEXYL ALKYL BENZAMIDES

Schedule 9

The proposed implementation date is 1 October 2017, as this is the earliest possible implementation date.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the recommendation comprised the following:

  • Independent expert advice regarding the appropriate naming of the group entries was received and is reflected in the proposed wording of the schedule entries.
  • The delegate acknowledges and agrees with the committee's advice:
    • There is a significant public health risk similar to other opioid analgesics, such as morphine and fentanyl, including abuse potential, dependence, toxicity and overdose. Furthermore, N,N-dialkylaminocyclohexyl alkyl benzamides and N,N-dialkylaminocyclohexylmethyl alkyl benzamides pose a risk of overdose.
    • There are no registered products, and there are no benefits from therapeutic use for N,N-dialkylaminocyclohexyl alkyl benzamides and N,N-dialkylaminocyclohexylmethyl alkyl benzamides.
    • Toxicity reports for N,N-dialkylaminocyclohexyl alkyl benzamides and N,N-dialkylaminocyclohexylmethyl alkyl benzamides are similar to other opioid analgesics such as fentanyl and morphine, which includes fatal overdose cases. There is also a significant potential for abuse similar to heroin and other illicit prescription and novel opioids.
    • There have been reports of illicit use. N,N-dialkylaminocyclohexyl alkyl benzamides and N,N-dialkylaminocyclohexylmethyl alkyl benzamides are also likely to have significant abuse liability given pharmacological profile. Although no animal studies are available to confirm this, the WHO report describes 'user reports' of tolerance and craving.
    • Since N,N-dialkylaminocyclohexyl alkyl benzamides and N,N-dialkylaminocyclohexylmethyl alkyl benzamides are obtained through illicit sources, the identity, purity, and quantity are uncertain, are inconsistent and therefore pose significant risks to the end-user.
    • There are no known medical or industrial uses.
    • Significant mortality has been noted internationally. They may be sold as heroin, or mixed with heroin, and this contributes to overdoses.

Footnotes

  1. U-47700: Everything You Need to Know About Deadly New Drug
  2. Loew, G.; Lawson, J.; Toll, L.; Frenking, G.; Berzetei-Gurske, I.; Polgar, W. (1988). Structure activity studies of two classes of β-amino-amides: the search for kappa-selective opioids (pdf,4,26Mb). NIDA Research Monograph. 90: 144-151. ISSN 1046-9516. PMID 2855852
    Szmuszkovicz, Jacob; Zhao, Shikai; Totleben, Michael J.; Mizsak, Stephen A.; Freeman, Jeremiah P. Phenanthridone Analogs of the Opiate Agonist U-47,700 in the trans-1,2-Diaminocyclohexane Benzamide Series". Heterocycles. 52 (1): 325-332. doi:10.3987/com-99-s27.
  3. U-47700 Critical Review Report Agenda Item 4.1
  4. Szmuszkovicz, Jacob (1999). U-50,488 and the κ receptor: A personalized account covering the period 1973 to 1990. Progress in Drug Research. Progress in Drug Research. Birkhäuser Basel. pp. 167-195.doi:10.1007/978-3-0348-8730-4_4. ISBN 9783034887304
    Tsibulnikov, S. Yu; Maslov, L. N.; Mukhomedzyanov, A. V.; Krylatov, A. V.; Tsibulnikova, M. R.; Lishmanov, Yu B. (October 2015). Prospects of Using of κ-Opioid Receptor Agonists U-50,488 and ICI 199,441 for Improving Heart Resistance to Ischemia/Reperfusion. Bulletin of Experimental Biology and Medicine. 159 (6): 718-721. doi:10.1007/s10517-015-3057-8. ISSN 1573-8221. PMID 26519268
  5. Buy Online U-47700 USA, EU, AU @ $35-$9 per g : ChingLabs; U-47700 buy U-47700 for sale online - $35.50 - Best-Feel.com

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