'He Ain't Heavy, He's My Brother' - Patents directed to deuterium modified drugs

Date: 2017-02-28

In this the fourth instalment of our series of articles1 looking at the hot topic of the patenting of radiopharmaceuticals, we are taking a small side-step away from the radioactive isotopes to look at the area of deuterated drugs or deuterium modification of known pharmaceuticals.

Rapid metabolism of pharmaceutical compounds

Many current pharmaceutical compounds have poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use. These poor ADME properties are a major reason for the failure of pharmaceutical compounds in clinical trials. It is possible to improve some ADME properties by using formulation technologies and prodrug strategies. However, these approaches often fail to address the underlying ADME problems that exist for many pharmaceutical compounds. One such problem is rapid metabolism that causes a number of pharmaceutical compounds, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid clearance is high or frequent dosing to attain a sufficiently high plasma level of the pharmaceutical compound. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. One potential strategy for improving a pharmaceutical compound’s metabolic properties is deuterium modification2.

Replacing hydrogen with deuterium

Deuterium (2H) is a stable, non-radioactive isotope of hydrogen. 2H forms stronger bonds with carbon compared to hydrogen. In some cases, the increased bond strength imparted by 2H can positively impact the ADME properties of a pharmaceutical compound, creating the potential for improved efficacy, safety, and/or tolerability of the pharmaceutical compound. At the same time, because the size and shape of 2H are essentially identical to those of hydrogen, replacement of hydrogen by 2H would not be expected to affect the biochemical potency and selectivity of the pharmaceutical compound as compared to the original chemical entity that contains only hydrogen3.

Patent landscape4

A summary of the major applicants and the main subject matters for the 2H patent landscape is given in Table 1, below.

Table 1. Overview of 2H pharmaceutical patent landscape 2006-2016.

Patent subject matter


Number of PCT applications

Deuterium modification of known pharmaceutical actives

Concert Pharmaceuticals, Inc.



Auspex Pharmaceuticals, Inc.


New compounds and their deuterated analogues

Almirall S.A.



Novartis AG



Schering Corporation



Concert Pharmaceuticals, Inc

The most prolific applicant in the area of deuterium modification and deuterated pharmaceuticals is Concert Pharmaceuticals, Inc.. Concert Pharmaceuticals, Inc. has a focus on creating novel drugs with improved properties by modifying compounds, which have established pharmacological activity, with deuterium. In the reviewed period, they filed 71 PCT applications directed to deuterated analogues or derivatives of known pharmaceutical actives/compounds. A selection of these applications is listed below.


  • Daclatasvir (WO2016089814)
  • Atazanavir metabolite derivatives (WO2012170792)
  • Etravirine (WO2009051782)
  • Darunavir (WO2009055006)
  • Elvitegravir derivatives (WO2009035662)
  • Dasabuvir (WO2016105547)


  • TIC10 (WO2016123183) 
  • OTX-015 (WO2016176335)
  • Pacritinib (WO2014159511)
  • Palbociclib (WO2014150925)
  • Lenalidomide isotopologues (WO2014110322)
  • Momelotinib (WO2014110189)
  • Ponatinib (WO2014028595)
  • Ibrutinib (WO2014022390)
  • Carfilzomib (WO2014011971)
  • Ruxolitinib derivatives (WO2013188783)
  • Rigosertib (WO2013159026)

Degenerative disorders

  • Preladenant (WO2012129381) 
  • Donepezil derivatives (WO2010019560)
  • Idebenone (WO2014012009)

Concert Pharmaceuticals, Inc. does not use a general method to modify the known pharmaceutical compound with deuterium; the method used varies from compound to compound. Often the method involves using a commercially available deuterated substructure of the compound, which then is further reacted to form the target compound. For instance, a deuterated analogue of the known drug Cilostazol (WO2008133949) is prepared using a commercially available cyclohexan-d11-ol as shown in Figure 1 below.


Figure 1. Reaction scheme for preparing a deuterated analogue of the known drug Cilostazol (WO2008133949).

Several of Concert Pharmaceuticals, Inc.’s modified compounds have reached the clinical trial phase of the product development. For instance, a deuterated version of Ivacaftor (CTP-656, WO2012158885) has reached Phase 2 trial in patients with cystic fibrosis5. Another example is a deuterated Apremilast analog (CTP-730, WO2010147922) for the potential treatment of inflammatory disease, where Phase 1 testing has been completed5.

Auspex Pharmaceuticals, Inc.

Another biopharmaceutical company that specializes in deuterium modification of known pharmaceutical compounds is Auspex Pharmaceuticals, Inc.. Auspex Pharmaceuticals, Inc., a subsidiary of Teva Pharmaceutical Industries Ltd. since 2015, is developing deutetrabenazine (SD-809, WO2014047167 and WO2015084622) for the potential treatment of chorea associated with Huntington’s disease, tardive dyskinesia, and Tourette syndrome. Deutetrabenazine is a deuterated analog of tetrabenazine (see Figure 2). Deutetrabenazine is the first deuterated compound to be reviewed by the U.S. Food and Drug Administration (FDA). The New Drug Application for deutetrabenazine was accepted by the FDA for the treatment of chorea associated with Huntington disease in August 2015. In May 2016, the FDA requested more data on deutetrabenazine, which were provided in the resubmission of the New Drug Application in October 2016. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) goal date of April 3, 20176.

Figure 2. Chemical structures of a) tetrabenazine and b) the deuterated analog detetrabenazine (WO2014047167 and WO2015084622).

Other known pharmaceutical compounds, which have been modified with deuterium by Auspex Pharmaceuticals, Inc. include:

  • Inhibitors of gastric H+, K+-ATPase, e.g. esomepraxole (WO2007041630)
  • Tadalafil derivatives (WO2007146124)
  • Amphetamines (WO2008016677)
  • Udenafil analogues (WO2008100886)
  • Venlafaxine and O-desmethylvenlafaxine (WO2008140859)
  • Pimavanserin (WO2008141057)
  • Zamifenacin derivatives (WO2008144602)

Deuterium switching

Modifying known pharmaceutical compounds by replacing hydrogens with deuterium is also known as “deuterium switching” and it is analogous to the “chiral switching” in which enantiomerically-enriched versions of existing racemic drugs are produced. Just as for patent applications directed to “chiral switching” compounds, patent applications directed to “deuterium switching” compounds are receiving an increasing number of inventive step objections as the prior art base is taking form3.  However, the unpredictability of the effect of deuteration on the pharmacokinetics and metabolism of a compound can often be used as an argument against inventive step objections.

New compounds as well

As a result of the wave of “deuterium switching” taking place, pharmaceutical companies are now also claiming deuterated versions of their new molecules. For instance, Novartis AG filed 15 PCT applications during the reviewed time period directed towards new compounds and their deuterated analogues. Seven of the 15 PCT applications are directed to compounds that are cyclin-dependent kinase inhibitors, which can be used for treating conditions such as cancers (WO2012101065, WO2012101062, WO2012066065, WO2012066070, WO2012101063, WO2012101064, WO2011101417). Another focus is on BACE inhibitors such as BACE1 (WO2011009943 and WO2012006953) and BACE2 (WO2012095521), which can be used to treat neurological disorders and metabolic disorders, respectively.

Similarly, Almirall S.A. filed 23 PCT applications in the reviewed time period directed towards new compounds and their deuterated analogues. Ten of the filed PCT applications are directed to compounds that are Janus Kinases inhibitors and can be used in treating e.g. asthma, chronic obstructive pulmonary disease, allergic rhinitis, allergic conjunctivitis, allergic dermatitis and atopic dermatitis (WO2011076419, WO2011101161, WO2011157397, WO2012041476, WO2012069202, WO2012160030, WO2013017461, WO2015086693, WO2015091531 and WO2016198663). Another focus is compounds that are M3 muscarinic antagonists useful for treating e.g. pulmonary diseases, glaucoma, neurological disorders, cardiac disorders, inflammation, gastrointestinal disorders, asthma, and chronic obstructive pulmonary disease (WO2011141180, WO2013068552, WO2013068554 and WO2014095920), and compunds that are CRTh2 antagonists useful for e.g. treating asthma, chronic obstructive pulmonary disease, dermatitis and allergic conjunctivitis (WO2012069175, WO2013010880, WO2013010881).

Other examples include the five PCT applications filed by Schering Corporation during the reviewed time period, which have claims directed to deuterated compounds or features (WO2012040048, WO2010068714, WO2009131975, WO2010042473 and WO2009131975).

There are many more examples of PCT applications similar to the ones above claiming deuterated known compounds or new compounds and their deuterated derivatives. However, due to the size restrictions of this article we have limited our discussion to giving you a few examples of what is currently being pursued in patents.

Closing remarks

The patent landscape of deuterated pharmaceutical compounds is currently dominated by deuterium switching where a known pharmaceutical compound is modified by replacing hydrogens with deuterium. There are some indications though that in the future we will see more applications claiming new pharmaceutical compounds and their deuterated derivatives. In the meantime, we are still waiting for the first deuterated pharmaceutical active to obtain regulatory approval, and until then it is unclear whether taking the deuterium “short cut” in pharmaceutical compound development has paid off.


1 Previous articles in this series:

  1. A hot couple in the patenting of radiopharmaceuticals - the theranostic pair Technetium-99m and Rhenium-188

  2. The 'teacher's PET" of radionuclides - patents directed to Flourine-18

  3. The new "PET" on the block: radioimaging with zirconium-89

2 Roger Tung, “The Development of Deuterium-Containing Drugs”, Innovations in Pharmaceutical Technology, 2010, issue 32.

3 Graham S Timmins, “Deuterated drugs: where are we now?”, Expert Opinion on Therapeutic Patents, 2014, 24(10): 1067-1075.

4 We conducted our patent search in Thomson Innovation limiting the search to PCT applications with an application date between 2006-01-01 and 2016-06-30 directed to deuteration of pharmaceuticals or deuterated drugs. The following search string was used: “CTB=(deuteration OR deuterated OR deuterium ADJ modification ) AND CTB=(pharmaceutical* OR drug*) AND PN=(WO) AND AD>=(20060101) AND AD<=(20160630);”. This search returned 376 patent applications, which were then reviewed for relevance and trends.

5 http://www.concertpharma.com/product-pipeline/

6 https://www.drugs.com/history/sd-809.html