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Usage

Uses

Used in Pharmaceutical Industry:
MILNACIPRAN HYDROCHLORIDE is used as an antidepressant medication for the treatment of serious depression. Its dual mechanism of action as a specific serotonin and noradrenaline reuptake inhibitor (SNRI) makes it superior to selective serotonin reuptake inhibitors (SSRI) like fluoxetine and fluvoxamine. It is effective in treating depression without the need for titrating drug doses, offering a more efficient and convenient treatment option for patients.

Mechanism of action

Milnacipran selectively inhibits the reuptake of 5-HT (selectivity ratio, 9) at the presynaptic membrane site, thus increasing the concentration of 5-HT in the synaptic cleft. Although milnacipran is not a TCA, its mechanism of action is similar to that of imipramine, and its binding and reuptake inhibition profile more closely resembles that of the TCAs. Milnacipran has weak affinity for adrenergic, muscarinic, and H1 receptors and, therefore, is expected to be devoid of the prominent side effects observed for the TCAs. In clinical studies, milnacipran showed antidepressant efficacy similar to that of TCAs and SSRIs.

Pharmacokinetics

In humans, milnacipran distinguishes itself from many other antidepressants by its simple pharmacokinetics. It is rapidly absorbed, with a high oral bioavailability, and it exhibits linear pharmacokinetics over a dose range of 25 to 200 mg/day. It circulates in the blood and distributes in the body principally as unmetabolized drug. Steady-state plasma levels are reached within 32 to 48 hours after twice-daily oral administration, and its metabolism does not involve the CYP enzyme system. Approximately 50% of the dose is excreted in urine as unmetabolized drug, and another 14% is excreted as its N-glucuronide conjugate. The remaining eliminated drug is composed of conjugated Phase I inactive metabolites. Because the unmetabolized drug is the only compound responsible for the activity of milnacipran, no dosage adjustment is needed in patients presenting liver impairment.

Clinical Use

(±)-Milnacipran is the ci s-aminomethyl derivative of phenylcyclopropanecarboxamide that acts by inhibiting both NE and 5-HT reuptake. It is structurally different from the other NSRIs and currently is only available in Europe as a racemic mixture, with both enantiomers exhibiting antidepressant activity. Substituting the aminomethyl group of milnacipran with an aminopropyl gives a milnacipran homologue that exhibits antidepressant activity as a potent N-methyl-D-aspartate (NMDA) receptor antagonist. A glutamate hypothesis is being investigated as an alternative mechanism of depression.

Side effects

Milnacipran has proven to be a very safe drug, with an adverse-event profile clearly superior to that of TCAs and, to a certain extent, that of SSRIs. Only approximately 10% of patients experience side effects, and only dysuria occurred more frequently (2%) with milnacipran than with TCAs or SSRIs. Milnacipran therefore appears to be an antidepressant with a very favorable benefit:risk ratio, although with a slower onset of action than the TCAs.

InChI:InChI=1/C15H22N2O/c1-3-17(4-2)14(18)15(10-13(15)11-16)12-8-6-5-7-9-12/h5-9,13H,3-4,10-11,16H2,1-2H3

Upstream product

• 105310-75-6 (1R,2R)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1-phenyl-cyclopropanecarboxylic acid diethylamide 
• 105310-75-6 (1SR,2RS)-2-((1,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-1-phenylcyclopropane carboxamide 
• 1237261-65-2 (1S,2R)-2-((1,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide-cyclopropanecarboxamide 
• 105310-90-5 (Z)-1-phenyl-2-(bromomethyl)-N,N-diethylcyclopropanecarboxamide 
• 140-29-4 phenylacetonitrile 
• 923037-67-6 Toluene-4-sulfonic acid (1R,2R)-2-diethylcarbamoyl-2-phenyl-cyclopropylmethyl ester 
• 131091-01-5 (1R,2R)-2-Hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide 
• 1353644-50-4 1-phenyl-1-diethylaminocarbonyl-2-chloromethylcyclopropane 
• 923037-67-6 C₂₂H₂₇NO₄S 
• 547-63-7 Methyl isobutyrate 
• 105310-09-6 milnacipran 
• 105-37-3 Ethyl propionate 

Downstream Products

• 1418000-39-1 N,N-diethyl-2-methyl-1-phenylcycloprop-2-enecarboxamide 
• 105310-06-3 2-(aminomethyl)-1-phenylcyclopropanecarboxamide 

Relevant academic research and scientific papers

Excretion and metabolism of milnacipran in humans after oral administration of milnacipran hydrochloride

The pharmacokinetics, excretion, and metabolism of milnacipran were evaluated after oral administration of a 100-mg dose of [14C] milnacipran hydrochloride to healthy male subjects. The peak plasma concentration of unchanged milnacipran (～240 ng/ml) was attained at 3.5 h and was lower than the peak plasma concentration of radioactivity (～679 ng Eq of milnacipran/ml) observed at 4.3 h, indicating substantial metabolism of milnacipran upon oral administration. Milnacipran has two chiral centers and is a racemic mixture of cis isomers: d-milnacipran (1S, 2R) and l-milnacipran (1R, 2S). After oral administration, the radioactivity of almost the entire dose was excreted rapidly in urine (approximately 93% of the dose). Approximately 55% of the dose was excreted in urine as unchanged milnacipran, which contained a slightly higher proportion of d-milnacipran (～31% of the dose). In addition to the excretion of milnacipran carbamoyl O-glucuronide metabolite in urine (～19% of the dose), predominantly as the l-milnacipran carbamoyl O-glucuronide metabolite (～17% of the dose), approximately 8% of the dose was excreted in urine as the N-desethyl milnacipran metabolite. No additional metabolites of significant quantity were excreted in urine. Similar plasma concentrations of milnacipran and the l-milnacipran carbamoyl O-glucuronide metabolite were observed after dosing, and the maximum plasma concentration of l-milnacipran carbamoyl O-glucuronide metabolite at 4 h after dosing was 234 ng Eq of milnacipran/ml. Lower plasma concentrations (25 ng Eq of milnacipran/ml) of N-desethyl milnacipran and d-milnacipran carbamoyl O-glucuronide metabolites were observed. Copyright

Milnacipran as a challenging example of aminomethyl substrate for lipase-catalyzed kinetic resolution

A biocatalysed procedure for the kinetic resolution of milnacipran, (±)-1 was developed and optimized by careful choice of the reaction parameters. The reaction of (±)-1 with methyl iso-butyrate as acyl donor in the presence of Novozyme 435 in tert-butyl

Preparation method of milnacipra hydrochloride intermediate

The invention provides a preparation method of an intermediate hydrochloride intermediate. Belong to chemical medicine preparation technical field. To the preparation method, the compound having the structure of the formula (II) is added into the methanol

Preparation of leveminacipran hydrochloride

The invention discloses a novel preparation method for synthesizing leveminacipran hydrochloride, and relates to a compound represented by a formula A. According to the invention, each step of reaction is simple in operation and mild in condition, use of

Chiral Bidentate Boryl Ligand Enabled Iridium-Catalyzed Enantioselective C(sp3)-H Borylation of Cyclopropanes

We herein report an Ir-catalyzed enantioselective C(sp3)-H borylation of cyclopropanecarboxamides using a chiral bidentate boryl ligand for the first time. A variety of substrates with α-quaternary carbon centers could be compatible in this reaction to provide β-borylated products with good to excellent enantioselectivities. We have also demonstrated that the borylated products can be used as versatile precursors engaging in stereospecific transformations of C-B bonds, including the synthesis of a bioactive compound Levomilnacipran.

Preparation method of levomilnacipran hydrochloride

The invention provides a preparation method of levomilnacipran hydrochloride. According to the preparation method, a mixed liquid is obtained through a mixed reaction of a compound adopting the structure shown in the formula (II) and alkali; then acid is

COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS

The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of neurological conditions may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of fibromyalgia, depression, neuropathic pain, severe pain, chronic pain, generalized pain, injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, post herpetic neuralgia, diabetic neuropathy, cancer pain, fibromyalgia and lower back pain.

PROCESS FOR PREPARING LEVOMILNACIPRAN

The present invention refers to a new process for preparing levomilnacipran, in particular to a process for the resolution of racemic tw-milnacipran with a derivative of optically active phenylglycine.

AN IMPROVED PROCESS FOR THE PREPARATION OF 1-ARYL 2-AMINOMETHYL CYCLOPROPANE CARBOXYAMIDE (Z) DERIVATIVES, THEIR ISOMERS AND SALTS

The present invention relates to an improved and one-pot process for the preparation of 1-Aryl 2-aminomethyl cyclopropane carboxyamide (z) derivatives, their isomers of formula (I) or its pharmaceutically acceptable salt thereof wherein R1 and R2 are represents independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, which aryl or alkylaryl group is optionally substituted by a halogen atom.

PROCESS FOR PREPARING LEVOMILNACIPRAN HCL

The invention relates to one-pot process for preparing (1S,2R)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-aminomethylcyclopropane of formula (I) comprising the step of reacting (1S,2R)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropanecarboxamide successively with the following reactants 1) triethyl orthoformate and methanesulfonic acid or triethylamine and methanesulfonyl chloride, 2) a phthalimidating agent, 3) aqueous EtNH2, wherein the reaction is carried out in toluene. In another aspect the invention concerns a process for preparing (1S,2R)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropanecarboxamide trough a step of crystallization of (1S,5R)-1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one.