53179-11-6 Usage
Uses
Loperamide is presently used more often as an antidiarrheal drug than as an analgesic, and
it is also included in the list of over-the-counter drugs because of its insignificant action on
the CNS. It reduces intestinal smooth muscle tone and motility as a result of binding to
intestinal opiate receptors. It is used for symptomatic treatment of severe and chronic diarrhea of various origins. The most popular synonym for loperamide is imodium.
Definition
ChEBI: A synthetic piperidine derivative, effective against diarrhoea resulting from gastroenteritis or inflammatory bowel disease.
Brand name
Ami-29;Colifelin;Colifilm;Diareze;Dissenter;Duplibiot;Elcoman;Firtasec;Loperan;Loperin;Lopermid;Motilix;Orulop;Pf 185;Pricilone;R-18553;Regulane;Seldiar;Taguinol;Telboc;Totrtasec.
Therapeutic Function
Antidiarrheal
World Health Organization (WHO)
Loperamide, an inhibitor of intestinal peristalsis, was introduced
in 1975 for the treatment of acute and chronic diarrhoea. In many countries its use
was discouraged in young children. In late 1989, treatment of infants in Pakistan
was associated with 19 cases of paralytic ileus, 6 of which have been fatal. This
has subsequently led the major manufacturer to withdraw all drop formulations of the drug worldwide as well as the lower dose syrup forms from countries where
there is a programme for the control of diarrhoeal diseases. The WHO Control of
Diarrhoeal Diseases Programme recommends that loperamide should not be used
in children below five year of age.
(Reference: (LJJ) Letter to WHO from Johnson & Johnson, , , 21 June 1990)
General Description
Loperamide (Imodium) is a 4-phenylypiperidine with amethadone-like structure attached to the piperidine nitrogen. It acts as an antidiarrheal by directly binding tothe opiate receptors in the gut wall. Loperamide inhibitsacetylcholine and prostaglandin release, decreasing peristalsisand fluid secretion thus increasing the GI transit time andreducing the volume of fecal matter.Loperamide is sufficiently lipophilic to cross the blood-brain barrier, yet itdisplays no CNS-opioid effects. The reason for this is that itis actively pumped out of the brain via the P-glycoproteinpump (MDR1). Knockout mice with the P-glycoproteinpump genetically removed were given radiolabeled loperamideand sacrificed 4 hours later. The [3H]loperamideconcentrations were measured and compared with wild-typemice. A 13.5-fold increase in loperamide concentration wasfound in the brain of the knockouts. In addition, the micelacking the P-glycoprotein pump displayed pronouncedsigns of central opiate agonism. Loperamide is availableas 2-mg capsules for treatment of acute and chronic diarrhea.Recommended dosage is 4 mg initially, with 2 mgafter each loose stool for a maximum of 16 mg/d.
Synthesis
Loperamide, 1-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-
piperidinebutyramide (3.1.55), proposed here as an analgesic, is synthesized by the alkylation of 4-(4-chlorophenyl)-4-hydroxypiperidine (3.1.50) using N,N-dimethyl(3,3-
diphenyltetrahydro-2-furylidene)ammonium bromide (3.1.54) in the presence of a base.
The 4-(4-chlorophenyl)-4-hydroxypiperidine (3.1.50) is synthesized by reacting
1-benzylpiperidine-4-one (3.1.48) with 4-chlorophenylmagnesiumbromide, followed by
debenzylation of the product (3.1.49) by hydrogenation using a palladium on carbon
catalyst.
The starting 1-benzylpiperidin-4-one (3.1.48) is synthesized by Dieckmann intermolecular condensation of N-benzyl-N,N-bis-(β-carboethoxyethyl)amine (3.1.46), which is easily
formed by reaction of benzylamine with ethyl acrylate to give 1-benzyl-3-carboethoxypiperidine-4-one (3.1.47) followed by acidic hydrolysis and thermal decarboxylation.N,N-Dimethyl-(3,3-diphenyltetrahydro-2-furyliden)ammonium bromide (3.1.54) is synthesized from diphenylacetic acid ethyl ester, which is reacted with ethylene oxide in the
presence of sodium hydroxide, giving 2,2-diphenylbutyrolactone (3.1.51). Reacting this
with hydrogen bromide in acetic acid opens the lactone ring, forming 2,2-diphenyl-4-bromobutyric acid (3.1.52). This transforms into acid chloride (3.1.53) using thionyl chloride,
which cyclizes upon further treatment with an aqueous solution of dimethylamine, thus
forming the desired N,N-dimethyl-(3,3-diphenyltetrahydro-2-furyliden)ammonium bromide (3.1.54). Reacting this with 4-(4-chlorphenyl)-4-hydroxypiperidine (3.1.50) gives the
desired loperamide (3.1.55) [34–36].
Veterinary Drugs and Treatments
Loperamide is used as a GI motility modifier in small animals. Use
in cats is controversial and many clinicians do not recommend using
in cats.
Check Digit Verification of cas no
The CAS Registry Mumber 53179-11-6 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 5,3,1,7 and 9 respectively; the second part has 2 digits, 1 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 53179-11:
(7*5)+(6*3)+(5*1)+(4*7)+(3*9)+(2*1)+(1*1)=116
116 % 10 = 6
So 53179-11-6 is a valid CAS Registry Number.
InChI:InChI=1/C29H33ClN2O2/c1-31(2)27(33)29(24-9-5-3-6-10-24,25-11-7-4-8-12-25)19-22-32-20-17-28(34,18-21-32)23-13-15-26(30)16-14-23/h3-16,34H,17-22H2,1-2H3
53179-11-6Relevant articles and documents
A high-yield route to synthesize the P-glycoprotein radioligand [ 11C]N-desmethyl-loperamide and its parent radioligand [ 11C]loperamide
Wang, Min,Gao, Mingzhang,Zheng, Qi-Huang
, p. 5259 - 5263 (2013/09/23)
N-Desmethyl-loperamide and loperamide were synthesized from α,α-diphenyl-γ-butyrolactone and 4-(4-chlorophenyl)-4- hydroxypiperidine in five and four steps with 8% and 16% overall yield, respectively. The amide precursor was synthesized from 4-bromo-2,2- diphenylbutyronitrile and 4-(4-chlorophenyl)-4-hydroxypiperidine in 2 steps with 21-57% overall yield. [11C]N-Desmethyl-loperamide and [ 11C]loperamide were prepared from their corresponding amide precursor and N-desmethyl-loperamide with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 20-30% and 10-15% radiochemical yields, respectively, based on [11C]CO2 and decay corrected to end of bombardment (EOB), with 370-740 GBq/μmol specific activity at EOB.
A chemoselective deoxygenation of N-oxides by sodium borohydride-Raney nickel in water
Gowda, Narendra B.,Rao, Gopal Krishna,Ramakrishna, Ramesha A.
experimental part, p. 5690 - 5693 (2010/11/05)
A simple and convenient protocol for deoxygenation of aliphatic and aromatic N-oxides to the corresponding amines in good to excellent yield using sodium borohydride-Raney nickel in water is reported. Other functional moieties such as alkenes, halides, ethers, and amides are unaffected under the present reaction condition.
Design and synthesis of 4-phenyl piperidine compounds targeting the mu receptor
Chen, Zhengming,Davies, Ellen,Miller, Wendy S.,Shan, Shen,Valenzano, Kenneth J.,Kyle, Donald J.
, p. 5275 - 5279 (2007/10/03)
Small molecule mu agonists based on the 4-phenyl piperidine scaffold were designed and synthesized to further investigate the therapeutic potential of loperamide analogs. The resulting compounds show excellent agonistic activity towards the human mu receptor with interesting SAR trends within the series. Small molecule mu agonists based on the 4-phenyl piperidine scaffold were designed and synthesized to further investigate the therapeutic potential of loperamide analogs. The resulting compounds show excellent agonistic activity towards the human mu receptor with interesting SAR trends within the series.
