Recently I posted on whether or not there is “a right structure for a compound“. I taked about trade names and registered chemical entities and posited the question regarding “whether a Registered Trade Name is absolute? I’m asking the question since I’m actually not sure. ”

There were two responses…

1) Rich Apodaca commented:”you’d probably find agreement among chemists that a trade name uniquely identifies one specific chemical entity. Ditto CAS Number.”

2) Peter Murray-Rust, as is his way (does anyone ever get a comment on their blog from PMR?), posted a detailed and thoughtful response on his own blog here.

I, like Rich, am of the opinion that a CAS Number does uniquely identify a specific chemical entity, not necessarily a unique structure. Of course, CAS numbers can be confusing too as I have commented here. Aspirin, for example, has 6 CAS numbers! So Rich and I agree on this…can anyone from CAS confirm or not whether our belief is right?

So, what about Trade Names? There were a number of purposeful errors in my original post to stimulate thought and feedback about my question. There is a LOT of confusion about identifiers and chemicals. The relationships are convoluted and even I struggle with certain aspects. So, let’s examine the confusions!.

I commented that “Zantac is a registered trade name for the chemical here. ” Check out the chemical structure there.

Now check out the Wikipedia text on that record view: “Ranitidine (INN) is a histamine H2-receptor antagonist that inhibits stomach acid production. It is commonly used in the treatment of peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD). It is currently marketed over the counter under the trade name Zinetac and Zantac by GlaxoSmithKline and by many other companies under various other names. ”

One might assume therefore that I am correct in my statement about Zantac. Check out the DailyMed label for Zantac here. This declares: “The active ingredient in ZANTAC Injection and ZANTAC Injection Premixed is ranitidine hydrochloride (HCl)”. Ah-ha…Zantac is a hydrochloride form of Ranitidine then? A search for Zantac gives THREE results on DailyMed…different in formulations but all pointing to the HCl form of ranitidine as the active component. So, based on this statement is it correct to label the structure here with the label Zantac? It doesn’t have the HCl so in theory, no. Is Wikipedia correct in saying that Ranitidine is “marketed over the counter as Zantac”. No. Hmmm. A conundrum? No. It’s clear. Zantac should ONLY be a Ranitidine HCl formulation. A couple of button clicks and the record now say Zantac (as HCl). But there are a LOT of other trade names associated with that Ranitidine record that don’t have such definitions (yet).

There is a Ranitidine Hydrochloride on ChemSpider here. It came as part of the recent CrystalEye deposition and is at this record. The associated publication is here, the title of the article is “Ranitidine hydrochloride, a polymorphic crystal form” and the abstract says:

” In the title compound, dimethyl({5-[2-(1-methylamino-2-nitroethenylamino)ethylthiomethyl]-2-furyl}methyl)ammonium chloride, C13H23N4O3S+·Cl-, protonation occurs at the dimethylamino N atom. The ranitidine molecule adopts an eclipsed conformation. Bond lengths indicate extensive electron delocalization in the N,N‘-dimethyl-2-nitro-1,1-ethenediamine system of the molecule. The nitro and methylamino groups are trans across the side chain C=C double bond, while the ethylamino and nitro groups are cis. The Cl- ions link molecules through hydrogen bonds.”

When I take the orientation information and draw the molecule from the crystal structure then I get:

and when I name this I get: (Z)-N-{2-[({5-[(dimethylamino)methyl]furan-2-yl}methyl)sulfanyl]ethyl}-N’-methyl-2-nitroethene-1,1-diamine, a Z-orientation.

Let’s return to Peter’s analysis of the list of identifiers associated with Ranitidine on the ChemSpider record in question. He comments

“PMR: ….. It is clear that

(Z)-N-{2-​[({5-[(Di​methylami​no)methyl​]furan-2-​yl}methyl​)sulfanyl​]ethyl}-N​’-methyl-​2-nitroet​hen-1,1-d​iamin

and

N-[2-[[[-​5-[(Dimet​hylamino)​methyl]-2​-furanyl]​methyl]th​io]ethyl]​-N’-methy​l-2-nitro​-1,1-ethe​nediamine

are not identical. One describes a compound whose stereochemistry is asserted, the other describes one where the stereochemistry is not asserted. Butene and 1-butene and 2-butene and (Z)-butene are all different. They all have different InChIs. Some of them may refer to the same concept in some contexts, but they are not synonyms. Fowler (Modern English Usage) says “perfect synonyms are extremely rare”.”

We are in absolute agreement about this issue. The names are not identical. One declares stereo and the other doesn’t. The question then is what synonyms are useful to the user of ChemSpider to locate the structure if they have a systematic name. One might assume that the more the merrier. There is an enormous number of variants of bracket styles and dashes that could give rise to probably dozens of names that are all consistent with the structure and the names shown come from different sources.

Additionally the comment is made “If we are representing something in a machine, and we assert the two are to be used interchangeably then we have to be very sure that they can be. Adding a “(Z)” may appear a reasonable thing to do – in this case it is a diastrous act that corrupts information.” This is the problem with identifiers – they are confounded with complexity and supports the concept that there are no absolutes in names associated with compounds.

In discussing Wikipedia Peter has previously pointed to Wikipedia as “Open, re-usable, very highly curated, and the first place that students look. That – or a derivative – is where the world’s chemistry should reside.” I have covered the complexity of Taxol/paclitaxel previously (1,2,3) so where does WIkipedia stand on Rantidine?

Wikipedia actually shows and names an E-orientation as shown below

So, Wikipedia says E, ChemSpider says Z- and no-specific stereochemistry (in its identifiers). The crystal structure specifies Z-stereo. Oh dear, what can the matter be?

I then searched PubChem and found 2E’s and a Z- under Zantac. I searched MeSH for ranitidine and found no stereo specified. I searched ChEBI for both ranitidine and zantac and found nothing.

Further down the rabbit hole we go…

PMR> “The robotic aggregation of chemical names and identifiers, if done without metadata and ontology, corrupts information. That’s a strong statement, but we can see it in the current case. First there is junk out there. Robotic name harvesting harvests junk. (Christoph Steinbeck described it in worse terms at the RSC meeting. ) Here’s a snip from page571454

Validated by Experts, Validated by Users, Non-Validated, Removed by Users, Redirected by Users, Redirect Approved by Experts

Ranitidine [Wiki]

(Z)-N-{2-​[({5-[(Di​m?thylami​no)m?thyl​]furan-2-​yl}m?thyl​)sulfanyl​]?thyl}-N​’-m?thyl-​2-nitro?t​h?ne-1,1-​diamine

(Z)-N-{2-​[({5-[(Di​methylami​no)methyl​]furan-2-​yl}methyl​)sulfanyl​]ethyl}-N​’-methyl-​2-nitroet​hen-1,1-d​iamin

The “?” characters show up in my browser – I don’t know what they are, but they are not normal “e”s (ASCII 101). The first name is not a synonym – I’m sorry, but it’s junk. Associating junk with good information degrades the good information rather than increasing the quality of the junk (There is a more formal proof somewhere by Shannon – I believe – that machines cannot act as 100% proofreaders).”

On a record view we list “Names and Synonyms”. The question marks Peter sees are for a French name shown here:

Looks fine in my broswer and pasted in here too: N-{2-[({5​-[(diméth​ylamino)m​éthyl]fur​an-2-yl}m​éthyl)sul​fanyl]éth​yl}-N’-mé​thyl-2-ni​troéthène​-1,1-diam​ine. So, not junk (saying that the French name is junk would offend the Parisians). Notice that the Z- has been removed (for now) and that the name is labeled French on the record. If any of you are seeing issues in your browser let us know and we will investigate at our end.

Further

“PMR: A trade name represents a product, not a compound and certainly not a connection table. In some cases it may refer to a pure substance, which itself is describable by a connection table, but these are not synonyms. And aggregating them as synonyms adds error rather than clarity. However there is an even stronger reason why “Zantac” does not describe ranitidine. See the FDA page. Zantac (Ranitidine Hydrochloride) Tablets Zantac contains (not “is”) ranitidine hydrochloride.”

A Trade Name DOES represent a product. It can represent MANY formulations also. The active component is commonly the material of interest that we would like to see as a connection table.

However, if one wants to find the active component in Zantac what would YOU do to find out? Type in Zantac on Wikipedia maybe? Look where it takes you: http://en.wikipedia.org/wiki/Zantac. So, Zantac redirects to Ranitidine..don’t forget the earlier statement about Wikipedia: “Open, re-usable, very highly curated, and the first place that students look. That – or a derivative – is where the world’s chemistry should reside.” Should the same be true for ChemSpider? I think so. But this is a choice we have to make to provide a service to the users.On MeSH a search on Zantac takes you to Ranitidine. On PubChem Zantac takes you to Ranitidine(s). So, association of Zantac with Ranitidine is appropriate BUT there is a need for ontologies, I agree. ChEBI has a good model for this (more later).

Interestingly, a search on Ranitidine on ChemSpider provides the following list of names:

PMR comments: “But the current aggregations of chemicals (Chemspider, eMolecules, Chempedia) are designed for use by machines as well as humans. And unless high-quality metadata is given, along with a structured ontology then machine aggregation of chemistry corrupts rather than enhances. For that reason we are building molecular repositories based on metadata and ontologies. In the current era of the web it’s becoming essential. ”

I  look forward to seeing how Zantac and Ranitidine are handled in this new world- if its a structured ontology then it sounds like an integration of MeSH with structures? Wikipedia is over 5000 organics now and is the culmination of thousands of hours of work by many dedicated individuals. And is not error-free. Any other efforts will be prone to similar issues so it’s going to be a major undertaking and I look forward to the results. The ChEBI team are already doing a good job in this area. You can see an ontology Tree View here. So, I’m definitely excited to see what will be better! Exciting times.

PMR comments? “Now, I suggested that the “(Z)” should not have been added to “ranitidine” to indicate the stereochemistry. You can find pages out there with “(E)”. What is the “correct structure”? Or is this a meaningless question?”

In my opinion this is NOT a meaningless question it is a good question. You saw what the crystal structure showed. SHould the name include stereochemistry? If so, when?

Please stay engaged in these discussions with both Peter and I. They are important and meaningful.

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One Response to “Zantac, Ranitidine and no absolutes in the names of compounds”

  1. sdg says:

    Names like Zantac are not mean for chemists. They are meant for doctors so they keep ordering the stuff when the patent expires rather than switching to a generic.

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