Gabapentin CAS 60142-96-3
Introduction：Basic information about Gabapentin CAS 60142-96-3, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Gabapentin Basic informationDescription Generic formulation Indications Dose titration Cautions Interactions Special populations Behavioural and cognitive effects in patients with epilepsy Psychiatric use
| Product Name: | Gabapentin |
| Synonyms: | NEURONTIN;GABAPENTINE;GABAPENTIN HYDROCHLORIDE;GABAPENTIN;GOE-3450;(1-AMINOMETHYL-CYCLOHEXYL)-ACETIC ACID;1-(AMINOMETHYL)CYCLOHEXANEACETIC ACID;AKOS 92109 |
| CAS: | 60142-96-3 |
| MF: | C9H17NO2 |
| MW: | 171.24 |
| EINECS: | 262-076-3 |
| Product Categories: | Miscellaneous Biochemicals;Ion channels;API;Pharmaceutical raw materials;ABILIFY;Other APIs;Organic acids;APIs;Intermediates & Fine Chemicals;Pharmaceuticals;API's;GABA/Glycine receptor;60142-96-3 |
| Mol File: | 60142-96-3.mol |
Gabapentin Chemical Properties
| Melting point | 162°C |
| Boiling point | 314.4±15.0 °C(Predicted) |
| density | 1.058±0.06 g/cm3(Predicted) |
| Fp | 9℃ |
| storage temp. | 2-8°C |
| solubility | H2O: 10 mg/mL |
| form | solid |
| pka | pKa1 (25°) 3.68; pKa2 10.70 |
| color | off-white |
| Water Solubility | water: 100mM |
| Merck | 14,4319 |
| BRN | 2359739 |
| BCS Class | 3 |
| Stability: | Stable for 1 year from date of purchase as supplied. Solutions in distilled water may be stored at -20°C for up to 3 months. |
| Major Application | pharmaceutical (small molecule) |
| InChI | 1S/C9H17NO2/c10-7-9(6-8(11)12)4-2-1-3-5-9/h1-7,10H2,(H,11,12) |
| InChIKey | UGJMXCAKCUNAIE-UHFFFAOYSA-N |
| SMILES | NCC1(CCCCC1)CC(O)=O |
| CAS DataBase Reference | 60142-96-3(CAS DataBase Reference) |
| EPA Substance Registry System | Cyclohexaneacetic acid, 1-(aminomethyl)- (60142-96-3) |
Safety Information
| Hazard Codes | T,Xi,F |
| Risk Statements | 61-36/37/38-39/23/24/25-23/24/25-11 |
| Safety Statements | 53-26-36/37/39-45-36-36/37-16 |
| RIDADR | UN3259 |
| WGK Germany | 3 |
| RTECS | GU6496000 |
| HazardClass | IRRITANT |
| HS Code | 29224999 |
| Storage Class | 3 - Flammable liquids |
| Hazard Classifications | Acute Tox. 3 Dermal Acute Tox. 3 Inhalation Acute Tox. 3 Oral Flam. Liq. 2 STOT SE 1 |
| Hazardous Substances Data | 60142-96-3(Hazardous Substances Data) |
| Description | Gabapentin is a second- generation antiepileptic drug (AED) known under the proprietary brand name of Neurontin® (Pfizer, New York, NY) in the UK and USA. |
| Generic formulation | MHRA/ CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (including generic products):
|
| Indications | Epilepsy: monotherapy or adjunctive therapy of focal seizures with or without secondary generalization.Recommendations summarized from NICE (2012)
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| Dose titration | Monotherapy or adjunctive therapy 300 mg od for day 1300 mg bd for day 2300 mg td for day 3 (or 300 mg td for day 1), then increased by 300 mg every 2– 3 days, divided into three doses; usual maintenance 900– 3600 mg daily, divided into three doses (max. 4800 mg daily) If gabapentin has to be discontinued, it is recommended this should be done gradually over a minimum of 1 week, independent of the indication. |
| Cautions |
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| Interactions | With AEDs Nil. With other drugs
With alcohol/food There are no known specific interactions between alcohol and gabapentin and there are no specific foods that must be excluded from diet when taking gabapentin. |
| Special populations | Renal impairment Reduce maintenance dose according to degree of reduction in creatinine clearance. Pregnancy
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| Behavioural and cognitive effects in patients with epilepsy | Gabapentin has a relatively favourable behavioural profile, although paradoxical hyperactivity, irritability and aggression have been occasionally reported, especially in patients with severe intellectual disabilities. The cognitive profile of gabapentin is equally favourable, as this AED has been associated with only minor cognitive difficulties (mainly in the attention domain). |
| Psychiatric use | Although gabapentin has no approved indications in psychiatry, it has shown efficacy in the treatment of anxiety disorders, especially social phobia. Other offlabel uses include other anxiety disorders (panic disorder, post- traumatic stress disorder), alcohol dependence and withdrawal, behavioural and psychological symptoms of dementia, and aggression. Gabapentin has also been proposed to be useful in the maintenance treatment of bipolar disorder as adjunctive therapy. |
| Description | Gabapentin was introduced in 1993 in the UK and early 1994 in the USA as anadjunctive therapy in the treatment of refractory partial seizures and secondarily generalizedtonic-clonic seizures. Although being a lipophilic analog of the neurotransmitter GABA,gabapentin appears to exert its anticonvulsive function by a GABA receptor independentmechanism, possibly involving the L-system amino acid transporter protein. Gabapentineasily crosses the blood brain barrier and exhibits a favorable pharmacokinetic profile withhigh tolerability. It does not interfere with the metabolism of other concomitant administeredantiepileptic drugs, thus having a low potential for drug interactions. Studies are currentlyunderway for the use of gabapentin as mono-therapy for the treatment of various seizures. |
| Description | γ- |
| Chemical Properties | White Crystalline Solid |
| Originator | Warner-Lambert (U.S.A.) |
| History | Gabapentin is a pharmacologically active amino acid, discovered by the pharmaceutical company Parke-Davis, now owned by Warner-Lambert, a division of Pfizer in 1974. Although it was first approved as a treatment for partial seizures in 1993, Pfizer pleaded guilty to illegally marketing gabapentin for unapproved uses in 2004 and was heavily fined by the US Department of Justice for defrauding public health care programs. When this adjunctive use was approved by the US Food and Drug Administration (FDA) in late 1993, Warner-Lambert released gabapentin under the brand name Neurontin, expecting it to make no more than $500,000. But the 2001 sales of Neurontin raked in $1.2 billion. |
| Uses | Gabapentin is an Amino acid structurally related to γ-Aminobutyric Acid (GABA), designed to cross the blood brain barrier. Used as an anticonvulsant. |
| Uses | selective H1-receptor antagonist |
| Uses | antipsychotic, 5HT2A antagonist |
| Uses | For the treatment of adult Restless Legs Syndrome (RLS) and postherpetic neuralgia (PHN). |
| Indications | Gabapentin (Neurontin) significantly decreases pain scores and sleep interferenceassociated with PHN. An initial dose of 300 mg/day is increasedover 4 weeks (900, 1,800, 2,400, 3,600 mg/day divided t.i.d.) until efficacyis obtained or side effects become intolerable. |
| Definition | ChEBI: Gabapentin is a gamma-amino acid that is cyclohexane substituted at position 1 by aminomethyl and carboxymethyl groups. Used for treatment of neuropathic pain and restless legs syndrome. It has a role as an anticonvulsant, a calcium channel blocker, an environmental contaminant and a xenobiotic. It is functionally related to a gamma-aminobutyric acid. |
| Manufacturing Process | 32.8 g 1,1-cyclohexane-diacetic anhydride are mixed with 7 g anhydrousmethanol and heated under reflux for 1 hour. After evaporation of the reactionmixture in a vacuum, was obtained 37.5 g monomethyl 1,1-cyclohexanediacetate in the form of a yellowish oil. 5.6 ml triethylamine in 16 ml anhydrous acetone are added dropwise at 0°C to a solution of 7.28 g monomethyl 1,1-cyclohexane-diacetate, then a solutionof 3.6 ml ethyl chloroformate in 16 ml anhydrous acetone is added thereto.The reaction mixture is further stirred for 30 min at 0°C and and then asolution of 3.4 g sodium azide in 12 ml water added dropwise thereto. Thereaction mixture is stirred for 1 hour at 0°C, then poured into ice water andextracted three times with 50 ml amounts of ice-cold toluene. The combinedextracts are dried over anhydrous sodium sulphate at 0°C and subsequentlyintroduced drop-wise into a flask pre-heated to 100°C. The mixture is thenheated for a further hour under reflux and thereafter evaporated in a vacuum.The crude methyl 1-isocyanatomethyl-1-cyclohexane-acetate which remainsbehind is heated under reflux for 3 hours with 50 ml 20% hydrochloric acid.After cooling the solution, it is extracted three times with 100 ml amounts ofchloroform to remove the 1-amino-methyl-1-cyclohexane-acetic acid lactamformed as a by-product product and the aqueous hydrochloric acid solutionevaporated in a vacuum, whereby 1-aminomethyl-1-cyclohexane-acetic acidcrystallises as the hydrochloride; m.p. 117-118°C, after recrystallisation fromacetone/methanol/ether. After recrystallization from methanol/ether themelting point of the product is 129-133°C. By treatment with a basic ion exchanger and crystallisation fromethanol/ether, there is obtained pure 1-amino-methyl-1-cyclohexane-aceticacid; melting point 162-166°C. |
| Brand name | Neurontin (ParkeDavis); Neurontin (Pfizer). |
| Therapeutic Function | Anticonvulsant |
| Biological Functions | Gabapentin (Neurotonin) was initially designed to be arigid analogue of GABA. When it was discovered tohave antiepileptic properties, it was assumed that thisactivity was related to a GABAergic mechanism.However, subsequent studies have failed to show anyGABAergic activity of gabapentin. Although it has notyet been possible to ascribe any definite mechanism toits antiepileptic activity, there is recent evidence that itmay function as an agonist at GABAB receptors in thebrain. Gabapentin is recommended as adjunctive therapyin the treatment of partial seizures in adults.When usedwith other drugs, it appears to be an effective AED; it isusually not effective when employed alone for patientswith severe seizures. Gabapentin is generally well tolerated, with somnolence,dizziness, and ataxia the most commonly reportedadverse effects. A low incidence of potentially serious side effects and no significant allergic reactions havebeen reported. |
| General Description | Gabapentin and its closely related analog pregabalin,(S)-3-isobutyl-GABA, are broad-spectrum anticonvulsantswith multiple mechanisms of action.24,51 Inaddition to modulating calcium influx and stimulateGABA biosynthesis as discussed earlier, they also competefor the biosynthesis of L-glutamic acid because oftheir structural similarity to L-leucine.51 Gabapentin andpregabalin have very little liability for causing metabolicbaseddrug–drug interactions, particularly when used incombination with other AEDs because they are not metabolizedin humans. More than 95% of the drug is excretedunchanged through the kidneys. However, there are somedifferences in their bioavailability. Unlike gabapentin,which exhibits 60% bioavailability when given in lowdoses because of intestinal uptake by a saturable smallneutral L-amino acid transporter, the absorption of pregabalinis almost complete (98%) and exhibits an ideal linear pharmacokinetic profile.24 This high bioavailability of pregabalincan be attributed to its closer structure similarity tothe essential amino acid, L-leucine. |
| Biological Activity | Anticonvulsant with several possible mechanisms of action. Increases GABA in the brain and binds to a novel site associated with voltage-sensitive Ca 2+ channels. Prevents neuronal death and is antinociceptive and anxiolytic. |
| Biochem/physiol Actions | Primary Targetα2δ subunit of L-type voltage gated Ca2+ channels |
| Clinical Use | Antiepileptic: Adjunctive treatment of partial seizures with orwithout secondary generalisation Neuropathic pain Migraine prophylaxis (unlicensed) |
| Side effects | Long-Term Side Effects of Gabapentin:
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| Side effects | Dose-limiting adverse effectsinclude somnolence, dizziness, ataxia, peripheral edema, and infection (22). |
| Synthesis | In the original synthesis(Goedecke) cyclohexenone is reacted withethyl cyanoacetate in the presence of ammoniato yield the Guareschi salt, which is hydrolyzedand decarboxylated to give 1,1-cyclohexanediaceticacid which is transformed by tothe corresponding anhydride with acetic anhydride.This anhydride is treated with methanol toyield the half ester 2-acetic acid, which is subjected to a Curtiustype rearrangement to give the isocyanate2-acetic acid.The desired compound is obtained by hydrolysisof 2-aceticacid with HCl, followed by hydrochloric salt removalvia anion exchange . |
| Veterinary Drugs and Treatments | Gabapentin may be useful as adjunctive therapy for refractory orcomplex partial seizures, or in the treatment of chronic pain in dogsor cats. |
| Drug interactions | Potentially hazardous interactions with other drugs Antacids: reduce absorption. Antidepressants: antagonism of anticonvulsive effect(convulsive threshold lowered); avoid with St John’swort. Antimalarials: anticonvulsant effect antagonised bymefloquine. Antipsychotics: antagonism of anticonvulsive effect(convulsive threshold lowered). Orlistat: possible increased risk of convulsions. |
| Metabolism | There is no evidence of gabapentin metabolism in humans.Gabapentin is eliminated unchanged solely by renalexcretion. |
| References | [1] JEN-KUN CHENG. Does gabapentin act as an agonist at native GABA(B) receptors?[J]. Journal of Biomedical Science, 2004, 11 3: 346-355. DOI:10.1007/bf02254439 [2] CHRISTOPHE LANNEAU . Gabapentin is not a GABAB receptor agonist[J]. Neuropharmacology, 2001, 41 8: Pages 965-975. DOI:10.1016/s0028-3908(01)00140-x [3] JAN HENDRICH. Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2008: 3628-3633. DOI:10.1073/pnas.0708930105 |
Gabapentin Preparation Products And Raw materials
| Raw materials | Sodium azide-->Ethyl chloroformate-->Cyclohexane-->Methanol-->Triethylamine |
