136434-34-9 Usage
Description
Duloxetine hydrochloride, also known as a selective serotonin (5-HT) and norepinephrine reuptake inhibitor (SNRI), is a pharmaceutical compound used for oral administration. It is currently approved in the US and Europe for the treatment of major depressive disorder (MDD) and diabetic peripheral neuropathic pain (DPN). Additionally, it is indicated for the treatment of stress urinary incontinence (SUI) in Europe. Duloxetine has a higher affinity for human norepinephrine and 5-HT transporters than its predecessor, venlafaxine, and shows a more balanced ratio of 5-HT to norepinephrine uptake inhibition. It is a moderate inhibitor of dopamine reuptake and shows only weak affinity for muscarinic, α1and α2 adrenergic, and histamine H1 receptors. Duloxetine is a white crystalline solid.
Uses
1. Used in Pharmaceutical Industry:
Duloxetine hydrochloride is used as an antidepressant for the treatment of major depressive disorder (MDD). It acts as a dual serotonin and norepinephrine reuptake inhibitor (SNRI), increasing the availability of neurotransmitters and ultimately increasing serotonergic and noradrenergic function within the central nervous system (CNS).
2. Used in Neuropathic Pain Treatment:
Duloxetine hydrochloride is used as an analgesic for the treatment of diabetic peripheral neuropathic pain (DPN). It inhibits the reuptake of serotonin and norepinephrine, thereby increasing their concentration in the CNS and providing pain relief.
3. Used in Urinary Incontinence Treatment (Europe):
Duloxetine hydrochloride is used as a treatment for stress urinary incontinence (SUI) in Europe. The increased neurotransmitter concentration is believed to increase the tone and contractions of the urethral sphincter at the opening of the bladder, helping to prevent accidental urine leakage.
4. Used in Antidepressant and Analgesic Applications:
Duloxetine hydrochloride is used as an anti-depressant and analgesic for osteoarthritis and musculoskeletal pain. It inhibits the reuptake of serotonin and norepinephrine, increasing their availability in the CNS and providing relief from pain and depression.
5. Used in Quality Control:
Duloxetine hydrochloride serves as pharmaceutical secondary standards for application in quality control, providing a convenient and cost-effective alternative to the preparation of in-house working standards for pharma laboratories and manufacturers.
6. Used in Leukotriene Antagonist and Antiasthmatic Applications:
Duloxetine hydrochloride is used as a leukotriene antagonist and antiasthmatic, potentially providing relief from asthma symptoms by inhibiting the action of leukotrienes, which are inflammatory mediators.
7. Used in Solubility Testing:
Duloxetine hydrochloride is soluble in water at a concentration of 5 mg/mL (clear solution, warmed), which can be useful for solubility testing and formulation development in the pharmaceutical industry.
Pharmacological effects
Duloxetine hydrochloride is the salt form of antidepressant drug duloxetine. It was successfully developed by Eli Lilly Company. Its pharmacological effect is the same as duloxetine. Duloxetine hydrochloride is a new kind of selective dual inhibitor of 5 hydroxy trptamine (5-HT) and norepinephrine reuptake, and thus having antidepressant effect, while also having inhibitory effect on the central pain. Its pharmacological characteristic is being able to inhibit neuronal pre-synaptic membrane’s reuptake on 5-hydroxy trptamine and norepinephrine but instead have a low inhibitory effect on the reuptake of dopamine. Duloxetine hydrochloride is indicated for depression and it is effective in treating both endogenous and non-endogenous depression as well as the feeling of pain associated with depression. It has a therapeutic dose of 60mg/d~120mg/d with a good security and fewer adverse reactions with common adverse reactions such as nausea, dry mouth, constipation, poor appetite, fatigue, sleepiness, and increased sweating. Another indication is the pain caused by diabetic neuropathy.
[Product Name] Cymbalta
[Alias] LY-264453, LY-248686
[Efficacy] antidepressant drug for treatment of stressful urinary incontinence.
[CAS]:136434-34-9
[Development Unit] Japan Shionogi Company, American company Eli-Lilly.
Duloxetine is a selective inhibitor for 5-HT and NE reuptake (SSNRI). The exact mechanism of the anti-depression duloxetine and central analgesic effect is not yet clear. It is thought that it is related to its reinforcing effect on the function of 5 hydroxy trptamine (5-HT) and norepinephrine in the central nervous system. The results of the clinical studies have shown that duloxetine is a strong inhibitor of the neuronal 5-HT and NE reuptake and has a relatively weak inhibitory effect on the reuptake of dopamine. In vitro studies have showed that duloxetine has no significant affinity to dopaminergic receptors, adrenergic receptors, cholinergic receptors, histamine receptors, opiate receptors, glutamate receptors, and the GABA receptors. Duloxetine does not inhibit monoamine oxidase.
Figure 1: The molecule formula of Duloxetine hydrochloride
Pharmacokinetics
Absorption and Distribution: oral administration of duloxetine hydrochloride enteric-coated capsules can yield a complete absorption with the average lag being two hours before the drug began to be absorbed (TLag). At 6 hours after oral administration, the duloxetine reaches maximum plasma concentration (Cmax) with eating causing no effects on the Cmax, but will delay the peak time to about 6 to 10 hours with slightly lower degree of absorption at about 10%. Compare the evening administration once with morning administration once, the absorption of duloxetine is delayed by 3 hours; apparent elimination increases by one thirds; the apparent volume of distribution is about 1640 L. Duloxetine has a high affinity (> 90%) to the human plasma proteins which mainly binds with albumin and α-acid glycoprotein. There has been no evaluation of whether there exist interactions between duloxetine with other high affinity protein binding drugs. Liver or renal insufficiency does not affect the binding between plasma protein and duloxetine.
Metabolism and Excretion: oral administration of C14-labeled duloxetine can be used to determine their in vivo biotransformation and degradation. The plasma duloxetine only account for about 3% of the total radiolabel, suggesting that duloxetine is extensively metabolized with many kinds of metabolites. The major biotransformation pathway of duloxetine includes naphthyl epoxidization after the binding and further oxidation. Among in vitro tests, CYP2D6 and CYPIA2 can both catalyze the epoxidation of naphthyl with the plasma product including glucuronide-bound 4-hydroxy duloxetine and sulfate-bound 5-hydroxy 6-methoxy duloxetine. It has been separated of various kinds of other metabolites from urine with some appearing only in the small elimination metabolic bypass. Only a small amount (about 1% of the oral dose) of non-metabolized duloxetine prototype is detected in the urine with the majority (about 70% of the oral dose) existing in the form of duloxetine metabolic product which is excreted in urine. About 20% of them is excreted through feces.
The above information is edited by the lookchem of Dai Xiongfeng.
Indications
It is used for the treatment of depression and the treatment of stress urinary incontinence.
In 2004, Japan Shionogi Pharmaceutical Co., Ltd. had obtained the authorization of Eli Lilly Company of US to perform further development on the duloxetine which has dual inhibitory effect on the reuptake of both 5 hydroxy trptamine (5-HT) and norepinephrine (NE). Existing studies have shown that this drug has certain efficacy in treating tension urinary incontinence, depression, and obesity. Currently, clinical trials of the drug for treatment of tension urinary incontinence and depression have all been completed.
Precautions
1. Liver and kidney dysfunction can significantly reduce the metabolism and clearance of duloxetine. Thus it is not recommended for such patients to apply duloxetine.
2. The interaction between duloxetine and alcohol may cause liver damage. Thus it is not generally recommended for the treatment of patients with alcoholism.
3. In the clinical trials, when compared with placebo, duloxetine causes the mean systolic blood pressure increase by 2mmHg, and the average diastolic blood pressure increase by 0.5mmHg. We recommend regular measurement of blood pressure both before and during treatment and therapy.
Drug Interactions
Duloxetine is metabolized through CYP2D6 and CYP1A2 metabolism with moderate inhibition of CYP2D6 but no inhibition and induction effects on CYP1A2 and CYP3A4. We should be cautious when apply it together with other drugs which are also metabolized through CYP2D6 and of narrow therapeutic window (such as: TCAs, Ic antiarrhythmic drugs, and phenothiazines).
Medication of Special Populations
[Medication of Pregnant women and lactating women] It is not clear whether it is safe when applied this drug for pregnant women of pregnancy category. Therefore, for pregnant women, they should weigh both the advantages and disadvantages to decide whether they should administrate this drug. Only with potential benefits higher than risks can they apply it. Otherwise, they should not administrate this drug during pregnancy and lactation period.
[Pediatric administration] There has been no enough clinical experience on the application on children.
[Elderly people] Clinical studies have not observed a significant difference of the security and efficacy between the elderly population and young population. But it can’t be exclude that the sensitivity of some elderly patients can be increased.
Contraindications
1. It should be contraindicated in patients known to be allergic to duloxetine or any of the inactive ingredients contained in the product.
2. It should be prohibited to apply it in combination with monoamine oxidase inhibitors (MAOIs). It is also not allowed to administrate this drug within 14 days after the withdrawal of MAOIs; According to the half-life of duloxetine, only after the five days of the withdrawal of duloxetine can the patients begin to administrate MAOIs.
3. Clinical trials have shown that duloxetine can increase the risk of mydriasis and therefore the angle-closure glaucoma patients without control should avoid applying duloxetine.
Originator
Lilly (US)
Biochem/physiol Actions
Duloxetine hydrochloride is a dual serotonin/norepinephrine reuptake inhibitor (SNRI), widely used clinically as an antidepressant and anxiolytic.
Synthesis
The
synthesis from Lilly’s group is depicted in Scheme 4.
Friedel-Crafts acylation of thiophene (24) by 3-
chloropropanoyl chloride (25) with SnCl4 as Lewis acid
gave ketone 26 which was then enantioselectively reduced
with (R )-1-methyl-3,3-diphenyl-tetrahydropyrrolo[1,2-
c][1,3,2]oxazaborole (27) in the presence of borane in THF
to give (S)-3-chloro-1-(2-thienyl)-1-propanol (28).
Compound 28 was subjected to Finkelstein reaction to give
(S)-3-iodio-1-(2-thienyl)-1-propanol which was reacted with
methylamine in THF to give compound 29. The alcohol 29
was then used in a nucleophilic displacement reaction with
1-fluoronaphthalene (30) in the presence of sodium hydride
in DMA to give duloxetine free base in 88% yield. Finally,
the free base was treated with HCl to yield duloxetine
hydrochloride (IV).
Check Digit Verification of cas no
The CAS Registry Mumber 136434-34-9 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,3,6,4,3 and 4 respectively; the second part has 2 digits, 3 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 136434-34:
(8*1)+(7*3)+(6*6)+(5*4)+(4*3)+(3*4)+(2*3)+(1*4)=119
119 % 10 = 9
So 136434-34-9 is a valid CAS Registry Number.
InChI:InChI=1/C18H19NOS.ClH/c1-19-12-11-17(18-10-5-13-21-18)20-16-9-4-7-14-6-2-3-8-15(14)16;/h2-10,13,17,19H,11-12H2,1H3;1H/t17-;/m1./s1
136434-34-9Relevant articles and documents
An Improved Process for Synthesis of (S)-Duloxetine Hydrochloride Involving Enzymatic Asymmetric Carbonyl Reduction on a Novel Ketoamine
Sasane, Sachin A.,Husain, Mofazzal,Bhise, Nandu B.,Singh, Girij P.,Joseph, Alex,Shenoy, Gautham G.
, p. 1 - 8 (2020/11/02)
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Anti-depression of the raw material preparation method
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, (2018/07/15)
The present invention discloses an anti-depression drug duloxetine hydrochloride - process improvement and optimization, which belongs to the field of biological medicine. Comprises the following main features: a) used in the Mannich reaction in N - methyl benzylamine hydrochloride, without the use of dimethylamine hydrochloride, so that the follow-up steps in the dealkylation reaction effect is better, yield is higher; b) without using any expensive chiral catalyst or a phase transfer catalyst, to use with high stability and high catalytic performance of metal catalyst; c) the better solvent for crystallization and to the solvent method, to avoid the harm of the residual solvent for crystallization; d) splitting the chiral compound in the dealkylation after, adopts a unique recrystallization technology, will split the mixture after separation, purity and relatively easy to assemble and disassemble the luminosity (S)- N - methyl - 3 - (1 - naphthoxy) - 3 - (2 - thienyl) propylamine/tartrate, so that the resulting duloxetine hydrochloride product can achieve a better therapeutic effect. The process of the invention clear, simple and convenient operation, mild reaction conditions, low production cost, is extremely beneficial to industrial production.
Preparation of duloxetine hydrochloride
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, (2017/08/26)
The invention belongs to the fields of organic chemistry and pharmaceutical chemistry, and particularly relates to a synthesis technique of duloxetine hydrochloride. By converting the R configuration compound into S configuration, compared with the duloxetine hydrochloride prepared from the single S-configuration compound, the total yield is enhanced by nearly 47%, and the production cost is lowered. 1-chloroethylchloroformate is used instead of phenyl chloro-formate to directly generate the duloxetine hydrochloride during demethylation, thereby reducing the salification step, shortening the production cycle and saving the cost.
