Pempidine is a
nicotinic antagonist
A nicotinic antagonist is a type of anticholinergic drug that inhibits the action of acetylcholine (ACh) at nicotinic acetylcholine receptors. These compounds are mainly used for peripheral muscle paralysis in surgery, the classical agent of this t ...
drug, first reported in 1958 by two research groups working independently, and introduced as an oral treatment for
hypertension
Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
.
Pharmacology
Reports on the "classical" pharmacology of pempidine have been published.
The Spinks group, at
ICI, compared pempidine, its ''N''-ethyl analogue, and
mecamylamine
Mecamylamine (INN, BAN; or mecamylamine hydrochloride (USAN); brand names Inversine, Vecamyl) is a non-selective, non-competitive antagonist of the nicotinic acetylcholine receptors (nAChRs) that was introduced in the 1950s as an antihypertens ...
in considerable detail, with additional data related to several structurally simpler compounds.
[
]
Toxicology
LD50 for the HCl salt of pempidine in mice: 74 mg/kg (intravenous
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
); 125 mg/kg (intraperitoneal
The peritoneum is the serous membrane forming the lining of the abdominal cavity or coelom in amniotes and some invertebrates, such as annelids. It covers most of the intra-abdominal (or coelomic) organs, and is composed of a layer of mesothe ...
); 413 mg/kg (oral
The word oral may refer to:
Relating to the mouth
* Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid
**Oral administration of medicines
** Oral examination (also known as an oral exam or ora ...
).[
]
Chemistry
Pempidine is an aliphatic
In organic chemistry, hydrocarbons ( compounds composed solely of carbon and hydrogen) are divided into two classes: aromatic compounds and aliphatic compounds (; G. ''aleiphar'', fat, oil). Aliphatic compounds can be saturated (in which all ...
, sterically hindered, cyclic, tertiary
Tertiary (from Latin, meaning 'third' or 'of the third degree/order..') may refer to:
* Tertiary period, an obsolete geologic period spanning from 66 to 2.6 million years ago
* Tertiary (chemistry), a term describing bonding patterns in organic ch ...
amine
In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...
, which is a weak base
A weak base is a base that, upon dissolution in water, does not dissociate completely, so that the resulting aqueous solution contains only a small proportion of hydroxide ions and the concerned basic radical, and a large proportion of undissocia ...
: in its protonated
In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), usually denoted by H+, to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a BrĂ ...
form it has a p''K''a of 11.25.[
Two early syntheses of this compound are those of Leonard and Hauck,][ These are very similar in principle: Leonard and Hauck reacted ]phorone
Phorone, or diisopropylidene acetone, is a yellow crystalline substance with a geranium odor, with formula or .
Preparation
It was first obtained in 1837 in impure form by the French chemist Auguste Laurent, who called it "camphoryle". In 1849, ...
with ammonia
Ammonia is an inorganic chemical compound of nitrogen and hydrogen with the chemical formula, formula . A Binary compounds of hydrogen, stable binary hydride and the simplest pnictogen hydride, ammonia is a colourless gas with a distinctive pu ...
, to produce 2,2,6,6-tetramethyl-4-piperidone, which was then reduced by means of the Wolff–Kishner reduction
The Wolff–Kishner reduction is a reaction used in organic chemistry to convert carbonyl functionalities into methylene groups. In the context of complex molecule synthesis, it is most frequently employed to remove a carbonyl group after it has ...
to 2,2,6,6-tetramethylpiperidine
2,2,6,6-Tetramethylpiperidine, abbreviated TMP, HTMP, or TMPH, is an organic compound of the amine class. In appearance, it is a colorless liquid and has a "fishy", amine-like odor. This amine is used in chemistry as a hindered base ( hindered am ...
. This secondary amine was then ''N''-methylated
Methylation, in the chemical sciences, is the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These term ...
using methyl iodide
Iodomethane, also called methyl iodide, and commonly abbreviated "MeI", is the chemical compound with the formula CH3I. It is a dense, colorless, volatile liquid. In terms of chemical structure, it is related to methane by replacement of one h ...
and potassium carbonate
Potassium carbonate is the inorganic compound with the formula . It is a white salt, which is soluble in water and forms a strongly alkaline solution. It is deliquescent, often appearing as a damp or wet solid. Potassium carbonate is mainly used ...
.[The boiling point of 147 °C given by these authors for their 1,2,2,6,6-pentamethylpiperidine is significantly below the range of approximately 182–188 °C reported by other chemists.]
Hall's method involved reacting acetone
Acetone (2-propanone or dimethyl ketone) is an organic compound with the chemical formula, formula . It is the simplest and smallest ketone (). It is a colorless, highly Volatile organic compound, volatile, and flammable liquid with a charact ...
with ammonia in the presence of calcium chloride
Calcium chloride is an inorganic compound, a Salt (chemistry), salt with the chemical formula . It is a white crystalline solid at room temperature, and it is highly soluble in water. It can be created by neutralising hydrochloric acid with cal ...
to give 2,2,6,6-tetramethyl-4-piperidone, which was then reduced under Wolff–Kishner conditions, followed by ''N''-methylation of the resulting 2,2,6,6-tetramethylpiperidine with methyl ''p''-toluenesulfonate.
References
External links
*
{{Nicotinic acetylcholine receptor modulators
Nicotinic antagonists
Piperidines
Reagents for organic chemistry