364782-34-3 Usage
Description
Cinacalcet is the first entry in a new class of therapeutic agents called the calcimimetics.
It was launched as an oral treatment for secondary hyperparathyroidism
(SHPT) in patients with chronic kidney disease on dialysis and for
hypercalcemia in patients with parathyroid carcinoma. SHPT is associated with
increased parathyroid hormone (PTH) secretion, which is triggered by low serum
levels of calcium resulting from the failure of the kidney to clear phosphorous from
the body and its inability to produce sufficient quantities of vitamin D. The consequences
of increased PTH include stimulation of osteoclastic activity, cortical
bone resorption and marrow fibrosis. PTH secretion is primarily regulated by the
calcium-sensing receptor (CaR), which is located on the surface of the chief cell of
the parathyroid gland. Calcimimetics bind to CaR and increase the sensitivity of
CaR to extracellular calcium, thereby enabling its activation at subnormal levels of
serum calcium. As a result, in the presence of these agents, the low levels of endogenous
calcium in patients with renal failure are able to exert a suppressive effect
on PTH secretion. Parathyroid carcinoma is also associated with elevated PTH
levels, which are driven by autonomous parathyroid gland activity and subsequently
lead to hypercalcemia. Although surgical resection is the primary therapy
for treating hypercalcemia in parathyroid carcinoma patients, calcimimetics offer a
nonsurgical alternative for patients with failed parathyroidectomy, metastatic
parathyroid carcinoma, or high surgical risk. The recommended dosage of
cinacalcet for the treatment of SHPT in chronic kidney disease is 30mg once daily
at start and subsequent titration to 60, 90, 120 or 180 mg once daily. The dosage for the treatment of hypercalcemia in patients with parathyroid carcinoma is 30 mg
twice daily at start and subsequent titration to 60 or 90 mg twice daily, or 90mg
three or four times daily as necessary to normalize serum calcium level. After oral
administration of cinacalcet, maximum plasma concentration is achieved in
approximately 2 to 6 hours. It has a terminal half-life of 30 to 40 hours and
steady-state drug levels are reached within 7 days. Cinacalcet has a high volume of
distribution (1000 L) and high protein binding (93%–97%). It is extensively metabolized
in the liver, mainly by CYP3A4, CYP2D6 and CYP1A2. The primary
routes of elimination are in the urine (80%) and in the feces (15%). In Phase III
clinical trials involving 1136 patients with SHPT, administration of cinacalcet at
30–180 mg/day doses for 6 months produced 38–48% decrease in intact PTH.
Overall, 64% of patients given cinacalcet achieved at least a 30% reduction in PTH,
versus 11% of placebo patients. Calcium-phosphorous product was reduced 14%
by the active treatment and did not change in the placebo group. In a much smaller
clinical study involving 21 hypercalcemic patients with parathyroid carcinoma, administration
of 60–360 mg/day doses of cinacalcet resulted in 71% of patients
achieving a target reduction of ≥1 mg/dL in serum calcium. The most common
adverse events in these trials were nausea and vomiting. In vitro, cinacalcet is a
strong inhibitor of CYP2D6; therefore, dose adjustments may be required when
coadministered with medications that are predominantly metabolized by CYP2D6
and have a narrow therapeutic index (e.g. flecainide, vinblastine, thioridazine and
most tricyclic antidepressants). Cinacalcet is prepared in a two-step synthesis starting
from 3-[3-(trifluoromethyl)phenyl]propionaldehyde, by first condensing with
(R)-(1-naphthyl)ethylamine to form the corresponding imine and subsequent
reduction of the imine with sodium cyanoborohydride.
Chemical Properties
Off-White to Tan Solid
Originator
NPS pharmaceuticals (US)
Uses
Cinacalcet hydrochloride can be used in clinical trial in secondary hyperparathyroidism.
Definition
ChEBI: A hydrochloride derived from equimolar amounts of cinacalcet and hydrogen chloride.
Synthesis
General
syntheses of this class of compounds have been published, however, the specific synthesis of cinacalcet (III) has
not been available to date. The synthesis of cinacalcet, based
on a patented procedure, is depicted in Scheme 3. A mixture
of 1-acetonaphthone (21), 3-trifluoromethyl-1-propylamine
(22) and titanium (IV) isopropoxide were stirred at rt to form
the enamine intermediate which was reduced with
methanolic sodium cyanoborohydride at rt to give
corresponding racemic a-methyl amine (23). Compound 23
was resolved and then treated with HCl etherate to give
cinacalcet hydrochloride (III) as a white solid.
references
[1] ure?a p1, fraz?o jm. calcimimetic agents: review and perspectives. kidney int suppl. 2003 jun;(85):s91-6.[2] colloton m1, shatzen e, wiemann b, starnes c, scully s, henley c, martin d.cinacalcet attenuates hypercalcemia observed in mice bearing either rice h-500 leydig cell or c26-dct colon tumors. eur j pharmacol. 2013 jul 15;712(1-3):8-15.
Check Digit Verification of cas no
The CAS Registry Mumber 364782-34-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 3,6,4,7,8 and 2 respectively; the second part has 2 digits, 3 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 364782-34:
(8*3)+(7*6)+(6*4)+(5*7)+(4*8)+(3*2)+(2*3)+(1*4)=173
173 % 10 = 3
So 364782-34-3 is a valid CAS Registry Number.
InChI:InChI=1/C22H22F3N.ClH/c1-16(20-13-5-10-18-9-2-3-12-21(18)20)26-14-6-8-17-7-4-11-19(15-17)22(23,24)25;/h2-5,7,9-13,15-16,26H,6,8,14H2,1H3;1H/t16-;/m1./s1
364782-34-3Relevant articles and documents
Preparation method of cinacalcet hydrochloride
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Paragraph 0035-0040, (2021/05/26)
The invention discloses a method for preparing cinacalcet hydrochloride. The method comprises the following steps: performing condensation reaction on m-trifluoromethyl benzaldehyde serving as a starting raw material and acetaldehyde to prepare m-trifluoromethyl cinnamyl aldehyde, directly obtaining an oxalate intermediate from the m-trifluoromethyl cinnamyl aldehyde and R-1-(1-naphthyl) ethyl amine by a one-pot method to avoid impurity increase caused by separation of an unstable intermediate namely imine, desalting oxalate, carrying out Pd/C catalytic hydrogenation to obtain cinacalcet, and carrying out a reaction on cinacalcet and hydrochloric acid to finally obtain cinacalcet hydrochloride. The synthesis method disclosed by the invention is green, environment-friendly, economical and practical, simple to operate and more beneficial to industrial production.
Preparation method of cinacalcet hydrochloride and intermediate thereof
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Paragraph 0054-0069, (2021/05/05)
The invention discloses a preparation method of cinacalcet hydrochloride and an intermediate thereof. The invention provides a cinacalcet II preparation method, which comprises: in a solvent, carrying out a reduction reaction on 3-(3-trifluoromethyl-phenyl)-N-(R)-(1-naphthyl-1-ethyl)-propanamide and a reducing agent, and after the reaction is completed, carrying out a quenching reaction by using a metal sulfate hydrate to obtain cinacalcet II, wherein the reducing agent is an alkali metal hydroboron and boron trifluoride system; the structural general formula of the hydrated sulfuric acid metal salt is Mx(SO4)y.zH2O, M is one or more of metal ions and ammonium radicals of a first period, a second period, a third period and a fourth period in a periodic table of elements, x is 1-2, y is 1-3, and z is 0-20. The preparation method is simple, high in safety, low in equipment requirement and suitable for industrial production, and the prepared cinacalcet hydrochloride product is high in purity and yield.
Preparation method of cinacalcet hydrochloride
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Paragraph 0029; 0046-0048; 0052-0053, (2020/10/05)
The invention relates to a preparation method of cinacalcet hydrochloride. The preparation method comprises the following steps: taking m-trifluoromethyl benzaldehyde, hydantoin and (R)-1-(1-naphthyl)ethylamine as raw materials, performing condensation, hydrolysis, amidation and reduction reaction to prepare cinacalcet, and reacting cinacalcet with hydrochloric acid to prepare cinacalcet hydrochloride. Compared with an existing synthesis method of cinacalcet hydrochloride, the preparation method is short in route and low in raw material cost, the adopted condensing agent is oxalyl chloride and thionyl chloride, which are low in price, the adopted reducing agent is sodium borohydride, which is low in price, a precious metal catalyst (palladium on carbon) is not used, the hydrogenation reaction step is avoided, the requirement for equipment is low, normal-pressure reaction operation can be adopted, and the method is suitable for large-scale industrial production.
