Osanetant (developmental code name SR-142,801) is a neurokinin 3 receptor

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

which was developed by

Sanofi-Synthélabo Sanofi S.A. is a French Multinational corporation, multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synth� ...

and was being researched for the treatment of

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...

but was discontinued. It was the first non-peptide NK₃ antagonist developed in the mid-1990s. Professor David J. Anderson, Director and Leadership Chair of the Tianqiao and Chrissy Chen Institute for Neuroscience at California Institute of Technology, has advocated that osanetant be explored as a treatment for pain, anxiety, and aggression in humans and companion animals experiencing bereavement or social isolation, citing research suggesting that osanetant has an excellent safety profile and suppresses negative effects of social isolation in mice through an evolutionarily-conserved mechanism and without acting as a depressant. Another potential application for osanetant is in the treatment of

drug addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use of ...

, as it has been found to block the effects of

cocaine Cocaine (from , from , ultimately from Quechuan languages, Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly recreational drug use, used recreationally for its euphoria, euphoric effects. It is primarily obtained from t ...

in animal models. Osanetant is being investigated by Acer Therapeutics as a treatment for severe vasomotor symptoms such as a hot flashes and flushes among people experiencing menopause.

Synthesis

Several different syntheses have been reported. Below are representative examples. Osanetant synthesis (Glaxo)

The reaction between 2-(3,4-Dichlorophenyl)-5-(tetrahydropyran-2-yloxy)pentanenitrile (1) and

methyl acrylate Methyl acrylate is an organic compound, more accurately the methyl ester of acrylic acid. It is a colourless liquid with a characteristic acrid odor. It is mainly produced to make acrylate fiber, which is used to weave synthetic carpets. It is al ...

(2) gives 4-Cyano-4-(3,4-dichlorophenyl)-7-(oxan-2-yloxy)heptanoic aci (3). Treatment with acid gives 3-

-(3,4-Dichlorophenyl)-2,6-dioxopiperidin-3-yl The hyphen-minus is the most commonly used type of hyphen, widely used in digital documents. It is the only character that looks like a minus sign or a dash in many character sets such as ASCII or on most keyboards, so it is also used as such. ...

ropyl acetate
CID:70104936
(4). Reduction of the imide with

Borane dimethylsulfide Borane dimethylsulfide (BMS) is a complexed borane reagent that is used for hydroborations and reductions. The advantages of BMS over other borane reagents, such as borane-tetrahydrofuran, are its increased stability and higher solubility. BMS ...

afforded 82621-51-8(5). The reaction of this intermediate with benzoyl chloride 8-88-4give
CID:22741724
(6). Treatment with mesyl chloride completed the synthesis o
CID:11812710
(7). Osanetant synthesis (Warner Lambert)

The reaction of 1-Benzyl-4-phenyl-4-piperidinol 3843-83-4(1) with

trimethylsilyl cyanide Trimethylsilyl cyanide is the chemical compound with the formula (CH3)3SiCN. This volatile liquid consists of a cyanide group, that is CN, attached to a trimethylsilyl group. The molecule is used in organic synthesis as the equivalent of hydrogen ...

and subsequent

Ritter reaction The Ritter reaction is a chemical reaction that transforms a nitrile into an ''N''-alkyl amide using various electrophilic alkylating reagents. The original reaction formed the alkylating agent using an alkene in the presence of a strong acid. M ...

gave N-(1-Benzyl-4-phenylpiperidin-4-yl)formamide
CID:10979305
(2). The reduction of the formamide with lithium aluminium hydride gave 1-benzyl-N-methyl-4-phenylpiperidin-4-amine 72734-03-1(3). Reaction with acetic anhydride gav
CID:22741820
(4). Catalytic hydrogenation removal of the benzyl protecting group gave N-Methyl-N-(4-phenylpiperidin-4-yl)acetamide 72733-87-8(5).

Convergent synthesis In chemistry a convergent synthesis is a strategy that aims to improve the efficiency of multistep synthesis, most often in organic synthesis. In this type of synthesis several individual pieces of a complex molecule are synthesized in stage one, ...

completes the synthesis of Osanetant.

CID:11119744

Subsequent studies have shown that the Osanetant precursor is already a powerful BAT (biogenic amine transporter) agent without the need for having to surmount the total synthesis of Osanetant. The Ki numbers in the patent for Ex 58 are NET = 2.4nM & DAT = 13.8nM. This is not the first time that Sanofi produced a 3-arylpiperidine having BAT dopaminergic properties. For example, 3- -(Trifluoromethyl)phenyliperidine 4321-45-5was reported in a previous patent.Lucien Nedelec, Jacques Guillaume, & Claude Dumont, (1981 to Sanofi Aventis France). It was stated in the patent that such compounds can be expected to be able to treat depression, obesity, and Parkinson's disease.

References

Acetamides Antipsychotics Benzamides Chloroarenes NK3 receptor antagonists Piperidines {{Nervous-system-drug-stub