133099-07-7 Usage
Description
Darifenacin hydrobromide, also known as Enablex, is a selective antagonist for the M3 muscarinic acetylcholine receptor. It is an orally active, once-a-day medication that is primarily used to treat overactive bladder symptoms such as urge urinary incontinence, urgency, and frequency. Darifenacin selectively inhibits the M3 receptor in the detrusor muscle while sparing the M1 and M2 receptors, which are believed to be involved in central nervous system and cardiovascular function, respectively. It is a white to almost white, crystalline powder with a molecular weight of 507.5 and is metabolized by the isozymes CYP2D6 and CYP3A4. Darifenacin hydrobromide is the hydrobromide salt of darifenacin and is available under the brand name Enablex by Novartis.
Uses
1. Urinary Incontinence Treatment:
Darifenacin hydrobromide is used as a medication for the treatment of urinary incontinence. It works by blocking the M3 muscarinic acetylcholine receptor, which is primarily responsible for bladder muscle contractions. This action helps to reduce the smooth muscle tone, allowing for a greater volume of urine to be stored in the bladder, resulting in less urinary incontinence, urgency, and frequency.
2. Overactive Bladder Management:
Darifenacin hydrobromide is used in the management of overactive bladder. It selectively inhibits contractions in isolated guinea pig ileum, bladder, and trachea, tissues that endogenously express high levels of M3 muscarinic acetylcholine receptors. This selective inhibition helps to reduce the symptoms of overactive bladder, such as urge incontinence, urgency, and frequency.
3. Acute Lymphoblastic Leukemia Therapy:
Although not a primary use, darifenacin hydrobromide has been studied for its potential therapeutic effects in acute lymphoblastic leukemia treatment. The exact mechanism of action in this context is not well-established, but it may involve the modulation of certain cellular pathways or interactions with other drugs used in cancer therapy.
4. Calcium Replenisher:
Darifenacin hydrobromide can also be used as a calcium replenisher, although this is not its primary application. The hydrobromide salt form of the compound may contribute to calcium levels in the body, which can be beneficial in certain medical conditions or situations where calcium supplementation is required.
Biochem/physiol Actions
Darifenacin hydrobromide is an antispasmodic muscarinic antagonist, selective for blocking the M3 muscarinic acetylcholine receptor, which is primarily responsible for bladder muscle contractions. Darifenacin hydrobromide has 9 and 12-fold greater affinity for M3 compared to M1 and M5, respectively, and 59-fold greater affinity for M3 compared to both M2 and M4. Darifenacin is used clinically to treat urinary incontinence and overactive bladder syndrome.
Synthesis
The synthesis of
darifenacin is depicted in Scheme 5. Commercially
available (2S,4R)-(-)-4-hydroxy-2-pyrrolidinecarboxylic acid
(17), anhydrous cyclohexanol and 2-cyclohexen-1-one were
heated at 154oC to give de-carboxylated compound 18 in 69
% yield. The 3-(R)-hydroxypyrrolidine (18) was N-tosylated
with p-toluenesulfonyl chloride in pyridine yielding compound
19 in 26 % yield . The N-tosylated alcohol 19 was
subjected to Mitsunobu reaction in the presence of methyl ptoluenesulfonate,
triphenylphosphine and diethyl azodicarboxylate
(DEAD) in THF to afford N-tosyl-3(S)-(tosyloxy)
pyrrolidine (20) in 70% yield, which was then condensed
with 2,2-diphenylacetonitrile with NaH in refluxing toluene
to give 2,2-diphenyl-2-[1-(p-toluenesulfonyloxy)pyrrolidin-
2(S)-yl]acetonitrile (21). The tosyl group of 21 was removed
with 48% HBr and phenol in refluxing water to yield 2,2-
diphenyl-2-[2(S)-pyrrolidinyl] acetonitrile as its corresponding
hydrogen bromide salt (22), which was coupled to 2-(2,
3-dihydrobenzofuran-5-yl) acetic acid (23) by treatment with
carbonyldiimidazole (CDI) in ethyl acetate to the corresponding
amide 24 in a quantitative yield. The amide (24)
was dissolved in toluene and reduced with sodium borohydride
in THF with slow addition of boron trifluoride THF complex to keep the temperature below 10°C to give free
amine in 88% yield. The free amine was converted to corresponding
hydrogen bromide salt (25) with 48% HBr in
methanol. Compound 25 was hydrolyzed with potassium
hydroxide in refluxing 2-methyl-butan-2-ol for twenty hours
to give acetamide which was crystallized from toluene as a
toluene solvated form in 84% yield. Finally, the toluene solvated
compound was converted to darfenacin hydrobromide
(IV) with 48% HBr in 2-methyl-butan-2-ol.
references
[1]. hegde ss1,choppin a,bonhaus d,briaud s,loeb m,moy tm,loury d,eglen rm.functional role of m2 andm3muscarinic receptorsin the urinary bladder of rats in vitro and in vivo.br j pharmacol.1997 apr;120(8):1409-18.[2]. brann mr1,ellis j,jrgensen h,hill-eubanks d,jones sv. muscarinicacetylcholinereceptorsubtypes: localization and structure/function.prog brain res.1993;98:121-7.[3]. miller dw1,hinton m,chen f.evaluation of drug efflux transporter liabilities of darifenacin in cell culture models of the blood-brain and blood-ocular barriers. neurourol urodyn.2011 nov;30(8):1633-8. doi: 10.1002/nau.21110. epub 2011 aug 8.[4]. haab f1,stewart l,dwyer p.darifenacin, anm3selectivereceptorantagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. eur urol.2004 apr;45(4):420-9; discussion 429.
Check Digit Verification of cas no
The CAS Registry Mumber 133099-07-7 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,3,3,0,9 and 9 respectively; the second part has 2 digits, 0 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 133099-07:
(8*1)+(7*3)+(6*3)+(5*0)+(4*9)+(3*9)+(2*0)+(1*7)=117
117 % 10 = 7
So 133099-07-7 is a valid CAS Registry Number.
InChI:InChI=1/C28H30N2O2.BrH/c29-27(31)28(23-7-3-1-4-8-23,24-9-5-2-6-10-24)25-14-17-30(20-25)16-13-21-11-12-26-22(19-21)15-18-32-26;/h1-12,19,25H,13-18,20H2,(H2,29,31);1H
133099-07-7Relevant articles and documents
Synthesis/Isolation of darifenacin hydrobromide by-products
Vasantha,Lakshmanarao,Srinivasa Rao,Sivalakshmi Devi,Venkata Suryanarayana
, p. 824 - 828 (2013/07/26)
During the process development in the laboratory, the purity of darifenacin hydrobromide has been tested by HPLC. Three byproduct peaks along with darifenacin 1 peak have been observed whose area percentage ranged from 0.06-0.20% by HPLC. As per the strin
AN IMPROVED PROCESS FOR THE PREPARATION OF DARIFENACIN HYDROBROMIDE
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, (2011/06/26)
The present invention relates to an improved process for the preparation of Darifenacin hydrobromide of Formula (I). (i) condensing 3-(S)-(-)-1l-carbamoyl-1,1-diphenylmethyl)pyrrolidine (III), or its salt, with a compound of Formula XIII in the presence of a. base in a solvent, wherein X represents Cl, Br, C1-3 alkyl sulfonate or C6-10 arγl sulfonate; to produce (S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3- pyrrolidinyl]-2,2-diphenylacetamide (Darifenacin) (Ia), (ix) treating (S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl]- 2,2-diphenylacetamide (Darifenacin) (Ia) with an acid in a solvent and water mixture, (x) isolating pure (S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3- pyrrolidinyl]-2,2-diphenylacetamide (Darifenacin) (Ia), (xi) treating pure Darifenacin (Ia) with HBr to produce Darifenacin hydrobromide (I).
Method for obtaining 1,3-difunctionalized pyrrolidine derivatives
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Page/Page column 17, (2010/10/19)
The present invention relates to a method for obtaining 1,3-difunctionalized pyrrolidine derivatives, such as 3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine, commonly known as Darifenacin, as well as to the i