75176-37-3 Usage
Description
Zofenoprilat, the active metabolite of Zofenopril, is a proline derivative characterized by its 4-(phenylsulfanyl)-L-proline structure, where the amine proton is replaced by a (2S)-2-methyl-3-sulfanylpropanoyl group. It is a white crystalline substance and functions as an angiotensin-converting enzyme (ACE) inhibitor.
Uses
Used in Pharmaceutical Industry:
Zofenoprilat is used as an ACE inhibitor for the treatment of hypertension and heart failure. It works by blocking the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, thereby reducing blood pressure and the workload on the heart.
Used in Cardiovascular Applications:
In the cardiovascular field, Zofenoprilat is utilized for its beneficial effects on the cardiovascular system. It helps in reducing the risk of heart attacks, stroke, and other cardiovascular events by lowering blood pressure and improving heart function.
Used in Renal Protection:
Zofenoprilat is also used in the context of renal protection, as it has been shown to have a protective effect on the kidneys by reducing the workload on the renal system and preventing the progression of kidney diseases in patients with hypertension and diabetes.
Used in Combination Therapy:
In combination with other medications, Zofenoprilat is used to enhance the overall therapeutic effect in treating various cardiovascular and renal conditions. This combination therapy can provide better control of blood pressure and improve the management of heart failure and other related conditions.
Originator
Zofenil arginine,Menarini
Manufacturing Process
Sodium metal (0.85 g, 0.037 mole) is dissolved in 40 ml of absolute ethanol.
To this there is added with stirring 3.7 ml (0.036 mole) of thiophenol followed
by 7.5 g (0.017 mole) of N-carbobenzyloxy-trans-4-tosyloxy-L-proline, methyl
ester [J. Am. Chem. Soc., 79, 191 (1957)]. After stirring for 4 h and standing
overnight at room temperature, the bulk of the ethanol is removed on a rotary
evaporator. The mostly solid residue is stirred with 120 ml of dichloromethane
and 60 ml of water. The layers are separated (some methanol is added to help
break up emulsions) and the aqueous phase is extracted with additional
dichloromethane (2x60 ml). The combined organic phase are washed with 100
ml of saturated sodium chloride solution, dried (MgSO 4 ), and the solvent
evaporated to give 6.5 g (100%) of N-carbobenzyloxy-cis-4-phenylthio-L-
proline, methyl ester as a pale yellow viscous oil.
The N-carbobenzyloxy-cis-4-phenylthio-L-proline, methyl ester (6.5 g, 0.017
mole) is dissolved in 55 ml of methanol, treated portionwise at -1° to 4°C
with 13 ml (0.026 mole) of 2 N sodium hydroxide, stirred at 0°C for 1 h, and
kept at room temperature for approximately 16 h. After removing about half
of the solvent on a rotary evaporator, the cooled solution is diluted with 100
ml of water, washed with 60 ml of ether (wash discarded), layered over with
70 ml of ethyl acetate, stirred, cooled, and acidified with 4.8 ml of 1:1
hydrochloric acid. After separating, the aqueous phase is extracted with
additional ethyl acetate (3x40 ml) and the combined organic layers are dried
(MgSO 4 ) and evaporated to give 5.9 g of a light yellow viscous oil. The latter
is dissolved in 30 ml of ethanol, treated with 1.9 g of cyclohexylamine in 3 ml
of ethanol and diluted to 330 ml with ether. On seeding, the crystalline
cyclohexylamine salt separates. The latter, after cooling for approximately 16
h, weighs 5.3 g; melting point 148-151°C. This material is combined with 1.5
g of identical product from a previous experiment, stirred with 200 ml of
boiling acetonitrile, and cooled to yield 6.3 g of colorless N-carbobenzyloxy-
cis-4-phenylthio-L-proline cyclohexylamine salt; melting point 152-155°C.
This N-carbobenzyloxy-cis-4-phenylthio-L-proline cyclohexylamine salt is
suspended in 25 ml of ethyl acetate, stirred, and treated with 25 ml of 1 N
hydrochloric acid. When two clear layers are obtained, they are separated and
the aqueous phase is extracted with additional ethyl acetate (3x25 ml). The
combined organic layers are dried (MgSO 4 ) and the solvent evaporated to give 5.0 g (65%) of N-carbobenzyloxy-cis-4-phenylthio-L-proline as a nearly
colorless, very viscous syrup.N-Carbobenzyloxy-cis-4-phenylthio-L-proline (4.9 g, 0.014 mole) is treated
with 25 ml of hydrogen bromide in acetic acid (30-32%), stoppered loosely,
and stirred magnetically. After 1 h the orange-yellow solution is diluted to 250
ml with ether to precipitate the product as a heavy oil which gradually
crystallizes on seeding, rubbing and cooling After stirring in an ice-bath for 1
h, the material is filtered under nitrogen, washed with ether, suspended in
fresh ether, cooled for approximately 16 h, and filtered again to give 3.2 g
(77%) of colorless solid (cis)-4-phenylthio-L-proline hydrobromide; melting
point 106-109°C.A solution of 3.0 g (0.0094 mole) of (cis)-4-phenylthio-L-proline hydrobromide
in 25 ml of water is stirred, cooled to 5°C and 15 ml of 20% sodium
carbonate are added. This mixture is treated with 2.0 g (0.011 mole) of D-3-
acetylthio-2-methylpropionyl chloride in 5 ml of ether during the course of 10
min with the intermittent addition of 3.0 g of sodium carbonate to maintain
the pH at 8.0 to 8.4). The mixture is stirred in the ice-bath for an additional
hour, 25 ml of water are added and then a solution of 5 ml of concentrated
hydrochloric acid in 25 ml of water. The strongly acid solution is saturated
with sodium chloride and extracted with 50 ml of ethyl acetate (four times).
The organic phases are combined, dried, filtered and solvent evaporated to
give 3.8 g of a pale yellow viscous oil. The dicyclohexylamine salt following
trituration with 15 ml of acetonitrile one obtains 2.4 g of colorless solid 1-[D-
3-(acetylthio)-2-methyl-1-oxopropyl]-cis-4-phenylthio-L-proline
dicyclohexylamine salt; melting point 184-186°C.
Therapeutic Function
Antihypertensive
Check Digit Verification of cas no
The CAS Registry Mumber 75176-37-3 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 7,5,1,7 and 6 respectively; the second part has 2 digits, 3 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 75176-37:
(7*7)+(6*5)+(5*1)+(4*7)+(3*6)+(2*3)+(1*7)=143
143 % 10 = 3
So 75176-37-3 is a valid CAS Registry Number.
InChI:InChI=1/C22H23NO4S2/c1-15(14-28-22(27)16-8-4-2-5-9-16)20(24)23-13-18(12-19(23)21(25)26)29-17-10-6-3-7-11-17/h2-11,15,18-19H,12-14H2,1H3,(H,25,26)/t15-,18-,19-/m0/s1
75176-37-3Relevant articles and documents
11C-Radiosynthesis and preliminary human evaluation of the disposition of the ACE inhibitor [11C]zofenoprilat
Matarrese, Mario,Salimbeni, Aldo,Turolla, Elia Anna,Turozzi, Damiano,Moresco, Rosa Maria,Poma, Davide,Magni, Fulvio,Todde, Sergio,Rossetti, Claudio,Sciarrone, Maria Teresa,Bianchi, Giuseppe,Kienle, Marzia Galli,Fazio, Ferruccio
, p. 603 - 611 (2007/10/03)
(4S)-1-[(S)-3-Mercapto-2-methylpropanoyl]-4-phenylthio-L-proline (Zofenoprilat, 2), the active metabolite of the potent ACE inhibitor Zofenopril Calcium (1), was labelled with carbon-11 (t1/2=20.4 min) to evaluate its pharmacokinetics behaviour in human body using Positron Emission Tomography (PET). [11C]2 labelling procedures were based on the use of immobilized Grignard reagent and the acylation of (S)-4-phenylthio-L-proline methyl ester (5) with 11C-labelled methacryloyl chloride, followed by a Michael addition with thiobenzoic acid. The radiochemical yield was 5-10% (EOB, decay corrected) and specific radioactivity ranged from 0.5 to 1.5 Ci/μmol (18.5-55.5 GBq/μmol). Preliminary in vivo human evaluation of [11C]2 showed that the drug accumulates in organs which express high levels of ACE, like lungs and kidneys, and in organs involved in drug metabolism such as the liver and gall bladder. Results of the distribution of [11C]2 showed a measurable concentration of the drug in the target tissues such as the kidney and to a minor extent, the heart, where it can afford organ protection.