CRL-40,940 (Flmodafinil), ≥98%

Chemical Information:

Technical Information:

Background:

CRL-40,940 (Flmodafinil, Lauflumide) is a derivative of Modafinil, a medication used for narcoleptics by increasing attention and reducing sleep cravings. CRL-40,940 is classified as a psychotonic and eugeroic and has demonstrated similar but somewhat more powerful effects than Modafinil in animal models.  

Chemically, CRL-40,940 (Lauflumide) is the bis(p-fluoro) derivative of Modafinil and is sometimes referred to as bisfluoromodafinil or Flmodafinil.[1]

Modafinil, Adrafinil, Flmodafinil (CRL-40,940), and CRL-40,941 are part of the same family of eugeroics that were initially discovered in the late 1970’s by Dr. Michel Jouvet’s French ‘Laboratorie Lafon’. At Lafon, the research team made several observations of the newly synthesized group of drugs. From their patent:

"In man, particularly old people, it was observed that ... CRL-40,940 ... administered in the form of gelules or tablets – each containing 100 to 200 mg of active ingredient, at the rate of 1 to 3 gelules or tablets per day –  have given excellent results as arousing medicaments."[2]

More recently, CRL-40,940 was patented again under a different name (Lauflumide). The patent describes Lauflumide as: 

“…[a] novel treatment for ADHD, narcolepsy and idiopathic hypersomnia that would provide better results than those obtained with current treatments based on psychostimulants, would treat symptoms resistant to current treatments with no symptom rebound effect, and would have a low toxicity.” [3]

The patent for Laufumide described an unexpected synthesis of a molecule that is similar to both Adrafinil and Modafinil but with greater efficacy than both the two molecules and with fewer side effects. Laufumide (2-((bis(4-fluorophenyl)methane)sulfinyl)acetamide) was explicitly described as not being related to amphetamine-like compounds and without any side effects of amphetamines. 

Furthermore, the patent described Flmodafinial (Lauflumide, CRL-40,940) as being 20 times more effective than Adrafinil and 4 times stronger than Modafinil. The researchers suggested that Lauflumide may present a novel therapeutic alternative to methylphenidate and amphetamine in ADHD and to modafinil in narcolepsy and idiopathic hypersomnia, with a long-lasting effectiveness in plasma of 6 to 7 hours. [4]

Unlike Adrafinil, CRL-40,941 also possesses interesting anti-aggressive properties in animal testing. In mice, the LD-0 (maximum non-lethal dose) of CRL 40,941 is higher than 512 mg/kg, and the LD50 is higher than 1024 mg/kg. [5]

Modes of action:

The modes of action by which Flmodafinil exerts its effects are thought to be complex and have not yet been fully elucidated. This holds true for both Modafinil and Adrafinil as well. The following description of Modafinil’s modes of action is from a 2011 study on the compound and several of its structural analogues:

“Several studies suggest that Modafinil modulates the activity of hypocretin, histamine, α-adrenergic, γ-aminobutyric acid (GABA), and/or glutamate receptors. Moreover, modafinil has been shown to bind the dopamine transporter (DAT) and block dopamine reuptake both in vitro and in vivo, although with low affinity as compared to cocaine. 

Recently, studies in human subjects, using positron emission tomography (PET), show Modafinil binding to the DAT, leading to speculation that Modafinil may have abuse potential. However, results of animal studies have been equivocal with at least one study of human stimulant abusers reporting cocaine-like effects of modafinil, whereas most studies indicate a low liability for abuse.” [6]

 Racemic (±) Modafinil showed Ki at the dopamine transporter (DAT) of 2520nM, while racemic Flmodafinil (CRL-40,940, Lauflumide) had Ki at the dopamine transporter (DAT) of 2190nM2.

Importantly, there may be a potential for analysis-related ambiguities when studying the chemical profile of CRL-40,940 using gas chromatography-mass spectrometry (GC-MS). A new study, published in 2017, found that 1,1,2,2-tetraphenylethane (TPE) was often formed due to thermal degradation of Flmodafinil during exposure to the heated GC injection port dissolved in a variety of solvents. The mechanism for this was:

“…Suggested to involve the generation of a benzhydrylium ion and its reaction with the sulfoxide oxygen of the parent compound to give an oxysulfonium intermediate”. [6]

Further Scientific research:

There is still room for further research into the effects of CRL-40,940, especially with regards to its effects in healthy humans. 

Clinical Reviews:

No clinical reviews have been put together on CRL-40,940 (Flmodafinil) due to a substantial lack of availability of data.

Human studies:

No studies with human participants have been published yet.

Toxicology cases:

No cases have been presented to date.

Animal studies:

According to the new patent for Lauflumide (CRL-40,940, Flmodafinil), it has significant superiority compared to Modafinil in the T-maze test.

According to the patent, the T-maze test is an effective method of testing the waiting ability of rats. In the T-maze test, rats are offered a choice between a quick and immediate food reward and a large but delayed reward. In adult Wistar rats, antidepressants like SSRIs and noradrenaline reuptake inhibitors increase the proportion of choices for large but delayed rewards, indicating an improvement in waiting ability (or a decrease in impulsivity). 

The impulsivity test is suitable for testing improvements made by drugs for the treatment of ADHD. An improvement in T-maze results shows that the drug reduces impulsivity and, consequently, could be used for the treatment of ADHD. Methylphenidate and d-amphetamine are used as a reference product in the same experiment.

In the experiment, Methylphenidate and d-amphetamine were used as reference products. In both the racemic form and the D form ((+) enantiomer), waiting ability in young Wistar rats was improved after 3 doses. Lauflumide was at least as effective as methylphenidate and d-amphetamine in improving waiting ability in young Wistar rats subjected to the T-maze test. Both Mazindol and Flmodafinil were more effective than Modafinil in improving waiting ability in the T-maze test. 

Interestingly, CRL-40,940 (Flmodafinil) is predicted to be the primary active metabolite of CRL-40,941 (Fladrafinil). In a similar fashion to CRL-40,940, this compound (CRL-40,941) was observed to have similar but more potent effects than Modafinil and Adrafinil. The research team at Laboratoires Lafon found that it had similar psychotonic and eugeroic properties to the two reference compounds but with two unique advantages: significant anti-aggressive properties and improved oral bioavailability. As a result, it was concluded that animal models presented CRL-40,940 and CRL-40,941 as being more potent than Adrafinil. [7]

Precaution and Disclaimer:
This Material is Sold For Research Use Only. Terms of Sale Apply.
Not for Human Consumption, nor Medical, Veterinary, or Household Uses.

References:

• [1] Acetamide, 2-[[bis(4-fluorophenyl)methyl]sulfinyl]-. (2018). PubChem Open Chemistry Database: U.S. National Library of Medicine, National Center for Biotechnology Information. Available online from: https://pubchem.ncbi.nlm.nih.gov/compound/13271852/ [Accessed 10 October 2017]
• [2] n.a. (n.d.). Patent application number CA1199916 A1. US Patent Office. Data provided by IFI CLAIMS Patent Services. Available online from: https://www.google.com/patents/CA1199916A1?cl=en 

• [3] Konofol E. (2011). Lauflumide and the enantiomers thereof, method for preparing same and therapeutic uses thereof: US 20130295196 A1. US Patent Office. Available online at: https://www.google.com/patents/US20130295196 [Accessed 10 October 2017]

• [4]  Cao J, Prisinzano TE, Okunola OM, et al. (2011). SARs at the Monoamine Transporters for a Novel Series of Modafinil Analogues. ACS Medicinal Chemistry Letters, 2(1):48-52. 
• [5] Lafon, L. (1986). Patent application number CA19830429261 19830531. US Patent Office. ESpaceNet Patent Search. Available online from: https://worldwide.espacenet.com/publicationDetails/biblio?CC=CA&NR=1199916
• [6] Dowling G, Kavanagh PV, Talbot B, O'Brien J, Hessman G, McLaughlin G, Twamley B, Brandt SD. (2017). Outsmarted by nootropics? An investigation into the thermal degradation of modafinil, modafinic acid, adrafinil, CRL-40,940 and CRL-40,941 in the GC injector: formation of 1,1,2,2-tetraphenylethane and its tetra fluoro analog, Drug Test Anal, 9(3):518-528. 
• [7] Lafon L. (1984). Patent Application number: US19830498592 19830526. US Patent Office. ESpaceNet Patent Bibliography. Available online from: https://worldwide.espacenet.com/publicationDetails/biblio?CC=US&NR=4489095&KC=&FT=E&locale=en_EP