102676-31-3 Usage
Description
Fadrozole hydrochloride, also known as Afema, is a non-steroidal imidazole derivative specifically designed for the treatment of post-menopausal breast cancer. It is a potent and specific aromatase inhibitor, characterized by its lack of androgenic or estrogenic activities due to its unique structural composition. Fadrozole hydrochloride functions by coordinating with the iron of the porphyrin nucleus, likely through the imidazole moiety, which leads to a strong binding that competes with the binding of molecular oxygen to iron, thereby reversibly inactivating the enzyme. This mechanism of action has resulted in an excellent clinical response rate with no significant side effects.
Uses
Used in Oncology:
Fadrozole hydrochloride is used as an antineoplastic agent for the treatment of post-menopausal breast cancer. Its potent and selective inhibitory effect on the aromatase enzyme system makes it a valuable tool in combating the disease by reducing the production of estrogen, a hormone that can fuel the growth of certain breast cancers.
Used in Pharmaceutical Industry:
Fadrozole hydrochloride is used as a pharmaceutical compound for the development of drugs targeting hormone-dependent cancers. Its specific action on the aromatase enzyme system allows for the creation of targeted therapies with minimal side effects, making it a preferred choice for drug development in the pharmaceutical industry.
Originator
Ciba-Geigy (Switzerland)
Manufacturing Process
5-p-Cyanophenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrochloride:A solution of 2.0 g of 4-(4-chloro-4-p-cyanophenyl-n-butyl)-1H-imidazole in
50 ml of chloroform is refluxed for 4 hours under nitrogen, cooled and
evaporated to yield the 5-p-cyanophenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrochloride; melting point 231-233°C (from 2-propanol).Preparation of the starting materials:A solution of 1.82 g of 4-(3-ethoxycarbonylpropyl)-1H-imidazole in 30 ml of
tetrahydrofuran under nitrogen is treated with 0.5 g of sodium hydride (50%
oil dispersion) at 0°C for 30 min and 1.45 ml of trimethylsilyl chloride at 0°C
for 3 hours. The reaction mixture is washed with cold 0.5 N sodium
bicarbonate solution, dried over sodium sulfate and evaporated to dryness.
The oil is redissolved in 100 ml of methylene chloride at -78°C under nitrogen
and 12.82 ml of diisobutylaluminum hydride (1.56 M) is added dropwise. The
reaction mixture is stirred for 5 min at -78°C, quenched with 1 ml of
methanol followed by 10 ml of water and filtered through Celite?. The organic
phase is separated, dried over sodium sulfate and evaporated to yield the title
compound (a).(b) 4-(4-p-t-Butylaminocarbonylphenyl-4-hydroxy-n-butyl)-1-trimethylsilylim
idazole:6.95 g of p-tert-butylaminocarbonylbromobenzene is dissolved in 175 ml of
tetrahydrofuran at -70°C under nitrogen and 20.1 ml of a solution of n-butyl
lithium (2.7 m) in hexane is added dropwise. After reacting 30 min, a solution
of 5.69 g of 4-(3-formyl-n-propyl)-1-trimethylsilyl imidazole in 10 ml of
tetrahydrofuran is added slowly. The reaction mixture is allowed to warm
slowly to room temperature and 20 ml of ammonium chloride is added. The
organic layer is separated, dried over sodium sulfate and evaporated to yield
the title compound (b).(c) 4-(4-Chloro-4-p-cyanophenyl-n-butyl)-1H-imidazole:A solution of 4.5 g of 4-(4-p-t-butylaminocarbonylphenyl-4-hydroxy-n-butyl)-
1-trimethylsilylimidazole in 50 ml of thionyl chloride is refluxed for 1 hour,
cooled and evaporated. The residue is partitioned between methylene chloride
and aqueous sodium bicarbonate solution. The organic phase is separated,
dried over sodium sulfate and evaporated to yield the title compound (c).5-p-Cyanophenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine:A solution of 2.0 g of 4-(4-chloro-4-p-cyanophenyl-n-butyl)-1H-imidazole in
50 ml of chloroform is refluxed for 4 hours under nitrogen, cooled and
evaporated to yield the 5-p-cyanophenyl-5,6,7,8-tetrahydroimidazo[1,5-
a]pyridine.
Therapeutic Function
Antineoplastic
Biochem/physiol Actions
Fadrozole is a nonsteroidal aromatase inhibitor. Fadrozole is a very potent and highly selective inhibitor of the aromatase enzyme system in vitro and estrogen biosynthesis in vivo. It inhibited the conversion of [4-14C]androstenedione to [4-14C]estrone by human placental microsomes in a competitive manner (Ki = 1.6 nM). At a substrate concentration 3-fold the Km, Fadrozole was 180 times more potent, as an inhibitor, than aminoglutethimide (Cat. No. A9657), exhibiting half-maximal inhibition at 1.7 nM as compared to 0.3 μM. In vivo, Fadrozole lowered ovarian estrogen synthesis by gonadotropin-primed, androstenedione treated, immature rats by 90% at a dose of 260 μg/kg (PO). In vivo, Fadrozole leads to sequelae of estrogen deprivation (e.g. regression of DMBA-induced mammary tumors) without causing adrenal hypertrophy in adult rats. It blocked aromatase by 50% in human breast cancer homogenates, live breast cancer cells, human placental microsomes, and porcine ovarian microsomes at concentrations of 0.008 to 0.02 μM.
Check Digit Verification of cas no
The CAS Registry Mumber 102676-31-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,0,2,6,7 and 6 respectively; the second part has 2 digits, 3 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 102676-31:
(8*1)+(7*0)+(6*2)+(5*6)+(4*7)+(3*6)+(2*3)+(1*1)=103
103 % 10 = 3
So 102676-31-3 is a valid CAS Registry Number.
InChI:InChI=1/C14H13N3.ClH/c15-8-11-4-6-12(7-5-11)14-3-1-2-13-9-16-10-17(13)14;/h4-7,9-10,14H,1-3H2;1H
102676-31-3Relevant articles and documents
Nickel-Catalyzed Reversible Functional Group Metathesis between Aryl Nitriles and Aryl Thioethers
Delcaillau, Tristan,Boehm, Philip,Morandi, Bill
supporting information, p. 3723 - 3728 (2021/04/07)
We describe a new functional group metathesis between aryl nitriles and aryl thioethers. The catalytic system nickel/dcype is essential to achieve this fully reversible transformation in good to excellent yields. Furthermore, the cyanide- and thiol-free reaction shows high functional group tolerance and great efficiency for the late-stage derivatization of commercial molecules. Finally, synthetic applications demonstrate its versatility and utility in multistep synthesis.
