23288-49-5

Basic information

• Product Name: Probucol
• Synonyms: PROBUCOL;4,4’-((1-methylethylidene)bis(thio))bis(2,6-bis(1,1-dimethylethyl)-pheno;biphenabid;bisbid;bisphenabid;dh581;4,4'-ISOPROPYLIDINEDITHIO-BIS-(2,6-DI-TERT-BUTYL)PHENOL;4-({1-[(4-hydroxy-3,5-di-t-butylphenyl)thio]-1-methylethyl}thio)-2,6-di-t-butylphenol
• CAS NO: 23288-49-5
• Molecular Formula: C₃₁H₄₈O₂S₂
• Molecular Weight: 516.84
• EINECS: 245-560-9
• Product Categories: Cardiovascular;Aromatics;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;API;LORELCO;Isolabel;Cardiovascular APIs
• Mol File: 23288-49-5.mol

Chemical Properties

• Melting Point: 126-128°C
• Boiling Point: 571.58°C (rough estimate)
• Flash Point: 264.9 °C
• Appearance: White Solid
• Density: 1.0008 (rough estimate)
• Vapor Pressure: 1.46E-12mmHg at 25°C
• Refractive Index: 1.5341 (estimate)
• Storage Temp.: Desiccate at +4°C
• Solubility: Chloroform (Slightly), Ethyl Acetate (Slightly)
• PKA: 10.27±0.70(Predicted)
• Merck: 14,7755
• CAS DataBase Reference: Probucol(CAS DataBase Reference)
• NIST Chemistry Reference: Probucol(23288-49-5)
• EPA Substance Registry System: Probucol(23288-49-5)

Safety Data

• WGK Germany: 2
• RTECS: AL3705000
• Hazardous Substances Data: 23288-49-5(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Probucol is used as an antihyperlipidemic agent for reducing high levels of cholesterol in blood. It accelerates the fractional rate of low-density (LDL) catabolism, which is the final pathway of cholesterol elimination inside the body. It may also inhibit the early stage of cholesterol biosynthesis and dietary cholesterol absorption.
Used in Treatment of Hyperlipoproteinemias:
Probucol is used as an antilipemic and anti-hyperlipoproteinemic agent for treating hyperlipoproteinemias characterized by elevated LDL levels. It reduces LDL and, to a lesser extent, HDL levels through a unique mechanism that is still not clearly delineated. The reduction of HDL may be caused by the ability of probucol to inhibit the synthesis of apoprotein A-1, a major protein component of HDL.
Used in Antioxidant and Anti-inflammatory Applications:
Probucol is used as an antioxidant, anti-inflammatory, and hypocholesterolemic agent which inhibits atherogenesis in murine models. Its strong antioxidant properties make it a promising candidate for various pharmaceutical applications.
Chemical Properties:
Probucol is a white solid with the brand name Lorelco (Sanofi Aventis). It is a dithioketal that is propane-2,2-dithiol in which the hydrogens attached to both sulfur atoms are replaced by 3,5-di-tert-butyl-4-hydroxyphenyl groups.

References

https://www.drugbank.ca/drugs/DB01599 https://pubchem.ncbi.nlm.nih.gov/compound/probucol#section=Top https://en.wikipedia.org/wiki/Probucol

Biological Functions

Probucol (Lorelco) is a hypocholesterolemic drug with few side effects that modestly (15–30%) decreases elevated plasma LDL cholesterol levels. The marginal LDL-lowering action plus reports that it can lower HDL cholesterol resulted in its discontinuation as a hypocholesterolemic drug. However, it still may reduce the risk of CHD because it is a powerful antioxidant. The oxidation hypothesis of atherosclerosis states that oxidation of lipids in LDL is required for LDL uptake by macrophages and smooth muscle cells in the intima of arteries, leading to their transformation to foam cells, an early event in atherogenesis. A recent clinical trial reported that use of probucol decreased the rate of restenosis of coronary arteries by 50% in patients who underwent angioplasty. Fluvastatin also has potent antioxidant properties that may contribute to its antiatherosclerotic effects.These findings suggest that reducing high plasma lipids may not be the only approach to retarding the progression of atherosclerosis and decreasing the risk of coronary heart disease.

Biological Activity

Antioxidant, anti-inflammatory and hypocholesterolemic agent. Inhibits atherogenesis in genetically hypercholesterolemic rabbits (Watanabe) and attenuates ischemia/reperfusion-induced cardiomyocyte apoptosis.

Mechanism of action

Probucol reduces the overall level of cholesterol—primarily low-density lipoproteins— without having an effect on triglycerides and very low-density lipoproteins. It has been suggested that it inhibits synthesis of cholesterol itself and increases removal of bile salts. Upon using this drug, a fraction of low-density proteins is reduced; however, even more significant is the reduction of high-density proteins. From the epidemiological point of view, this is dangerous, because lowering the concentration of high-density proteins means less cholesterol is removed from tissues. However, in any case, probucol lowers the level of cholesterol in the plasma by 10–15%. Moreover, it has been shown that probucol facilitates reduction of necrotic zones in myocardial ischemia.

Pharmacology

Being a lipophilic compound, it is easily distributed into fatty tissue and, as a result, approximately 20% of its maximum concentration in the blood is still maintained for 6 months.

Synthesis

Probucol, bis(3,5-tert-butyl-4-hydroxyphenyl)mercaptol acetone (20.2.6), is synthesized by thioketalizing acetone with 2,6-di-tert-butyl-4-mercaptophenol in the presence of hydrogen chloride.

InChI:InChI=1/C31H48O2S2/c1-27(2,3)21-15-19(16-22(25(21)32)28(4,5)6)34-31(13,14)35-20-17-23(29(7,8)9)26(33)24(18-20)30(10,11)12/h15-18,32-33H,1-14H3

Upstream product

• 950-59-4 4-hydroxy-3,5-di-tert-butylthiophenol 
• 67-64-1 acetone 

Downstream Products

• 216167-82-7 probucol monosuccinate 
• 216168-45-5 AIf₁ 
• 216167-92-9 2-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetic acid 
• 216167-95-2 butanoic acid, 4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)4-hydroxyphenyl]thio]-1-methylethyl]-thio]-2,6-bis(1,1-dimethylethyl)phenoxy] 
• 216168-60-4 (2-{2,6-di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-hydroxyphenylsulfanyl)-1-methylethylsulfanyl]phenoxy}acetylamino)acetic acid ethyl ester 

Relevant articles and documents

METHODS FOR PRODUCING 2,6-DI-TERT-BUTYL-4-MERCAPTOPHENOL AND 4,4'-ISOPROPYLIDENEDITHIOBIS[2,6-DI-TERT-BUTYLPHENOL]

The present invention provides a method for producing 2,6-di-tert-butyl-4-mercaptophenol containing reducing bis(3,5-di-tert-butyl-4-hydroxyphenyl) polysulfide with zinc in a mixed solvent of toluene and n-butanol, and provides a method for producing 4,4'-isopropylidenedithiobis[2,6-di-tert-butylphenol] using the above-mentioned method.

Process for preparation of probucol derivatives

A method is described for the preparation of polymorphic forms of water-soluble derivatives of probucol compounds having the following formula where R1, R2, R3, R4, R5, R6, Z and Z′ are defined herein.

Carotenoid ester analogs or derivatives for controlling C-reactive protein levels

A method of controlling (e.g., influencing or affecting) C-reactive protein levels in a subject may include administering to the subject an effective amount of a pharmaceutically acceptable formulation. The pharmaceutically acceptable formulation may include a synthetic analog or derivative of a carotenoid. The subject may be administered a carotenoid analog or derivative, either alone or in combination with another carotenoid analog or derivative, or co-antioxidant formulation. The carotenoid analog may include a conjugated polyene with between 7 to 14 double bonds. The conjugated polyene may include a cyclic ring including at least one substituent. In some embodiments, a cyclic ring of a carotenoid analog or derivative may include at least one substituent. The substituent may be coupled to the cyclic ring with an ester functionality.

Carotenoid analogs or derivatives for controlling C-reactive protein levels

A method of controlling (e.g., influencing or affecting) C-reactive protein levels in a subject may include administering to the subject an effective amount of a pharmaceutically acceptable formulation. The pharmaceutically acceptable formulation may include a synthetic analog or derivative of a carotenoid. The subject may be administered a carotenoid analog or derivative, either alone or in combination with another carotenoid analog or derivative, or co-antioxidant formulation. The carotenoid analog may include a conjugated polyene with between 7 to 14 double bonds. The conjugated polyene may include an acyclic alkene including at least one substituent and/or a cyclic ring including at least one substituent. In some embodiments, a carotenoid analog or derivative may include at least one substituent.

Pharmaceutical compositions including carotenoid ether analogs or derivatives for the inhibition and amelioration of disease

A method for inhibiting and/or ameliorating the occurrence of diseases associated with reactive oxygen species, reactive nitrogen species, radicals and/or non-radicals in a subject whereby a subject is administered a carotenoid analog or derivative, either alone or in combination with another carotenoid analog or derivative, or co-antioxidant formulation. The analog or derivative is administered such that the subject's risk of experiencing diseases associated with reactive oxygen species, reactive nitrogen species, radicals and/or non-radicals may be thereby reduced. The analog or analog combination may be administered to a subject for the inhibition and/or amelioration of any disease that involves production of reactive oxygen species, reactive nitrogen species, radicals and/or non-radicals. In some embodiments, the invention may include a pharmaceutical composition including a carotenoid analog or derivative. The carotenoid analog may include a conjugated polyene with between 7 to 14 double bonds. The conjugated polyene may include a cyclic ring including at least one substituent. In some embodiments, a cyclic ring of a carotenoid analog or derivative may include at least one substituent. The substituent may be coupled to the cyclic ring with an ether functionality. In some embodiments, a pharmaceutical composition may include a biologically inactive carrier. The pharmaceutical composition may be adapted to be administered to a human subject.

Pharmaceutical compositions including carotenoid ester analogs or derivatives for the inhibition and amelioration of disease

A method for inhibiting and/or ameliorating the occurrence of diseases associated with reactive oxygen species, reactive nitrogen species, radicals and/or non-radicals in a subject whereby a subject is administered a carotenoid analog or derivative, either alone or in combination with another carotenoid analog or derivative, or co-antioxidant formulation. The analog or derivative is administered such that the subject's risk of experiencing diseases associated with reactive oxygen species, reactive nitrogen species, radicals and/or non-radicals may be thereby reduced. The analog or analog combination may be administered to a subject for the inhibition and/or amelioration of any disease that involves production of reactive oxygen species, reactive nitrogen species, radicals and/or non-radicals. In some embodiments, the invention may include a pharmaceutical composition including a carotenoid analog or derivative. The carotenoid analog may include a conjugated polyene with between 7 to 14 double bonds. The conjugated polyene may include a cyclic ring including at least one substituent. In some embodiments, a cyclic ring of a carotenoid analog or derivative may include at least one substituent. The substituent may be coupled to the cyclic ring with an ester functionality. In some embodiments, a pharmaceutical composition may include a biologically inactive carrier. The pharmaceutical composition may be adapted to be administered to a human subject.

Carotenoid ester analogs or derivatives for the inhibition and amelioration of liver disease

A method of treating liver disease in a subject may include administering to the subject an effective amount of a pharmaceutically acceptable formulation. The pharmaceutically acceptable formulation may include a synthetic analog or derivative of a carotenoid. The subject may be administered a carotenoid analog or derivative, either alone or in combination with another carotenoid analog or derivative, or co-antioxidant formulation. The carotenoid analog may include a conjugated polyene with between 7 to 14 double bonds. The conjugated polyene may include a cyclic ring including at least one substituent. In some embodiments, a cyclic ring of a carotenoid analog or derivative may include at least one substituent. The substituent may be coupled to the cyclic ring with an ester functionality.

Carotenoid analogs or derivatives for the inhibition and amelioration of disease

A method for inhibiting and/or ameliorating the occurrence of diseases associated with reactive oxygen species, reactive nitrogen species, radicals and/or non-radicals in a subject whereby a subject is administered a carotenoid analog or derivative, either alone or in combination with another carotenoid analog or derivative, or co-antioxidant formulation. The analog or derivative is administered such that the subject's risk of experiencing diseases associated with reactive oxygen species, reactive nitrogen species, radicals and/or non-radicals may be thereby reduced. The analog or analog combination may be administered to a subject for the inhibition and/or amelioration of any disease that involves production of reactive oxygen species, reactive nitrogen species, radicals and/or non-radicals. In some embodiments, the invention may include a chemical compound including an analog or derivative of a carotenoid. The carotenoid analog or derivative may be synthetic. The carotenoid analog may include a conjugated polyene with between 7 to 14 double bonds. The conjugated polyene may include an acyclic alkene including at least one substituent and/or a cyclic ring including at least one substituent. In some embodiments, a carotenoid analog or derivative may include at least one substituent. The substituent may enhance the solubility of the carotenoid analog or derivative such that the carotenoid analog or derivative at least partially dissolves in water.

Carotenoid analogs or derivatives for the inhibition and amelioration of ischemic reperfusion injury

A method of treating ischemic reperfusion injury in a subject. The method may include administering to the subject an effective amount of a pharmaceutically acceptable formulation. The pharmaceutically acceptable formulation may include a synthetic analog or derivative of a carotenoid. The subject may be administered a carotenoid analog or derivative, either alone or in combination with another carotenoid analog or derivative, or co-antioxidant formulation. The carotenoid analog may include a conjugated polyene with between 7 to 14 double bonds. The conjugated polyene may include an acyclic alkene including at least one substituent and/or a cyclic ring including at least one substituent. In some embodiments, a carotenoid analog or derivative may include at least one substituent.

Carotenoid ether analogs or derivatives for controlling connexin 43 expression

A method of controlling (e.g., influencing or affecting) connexin 43 expression in a subject may include administering to the subject an effective amount of a pharmaceutically acceptable formulation. In some embodiments, controlling connexin 43 expression in a subject may effectively treat cardiac arrhythmia and/or cancerous and pre-cancerous cells in a subject. The pharmaceutically acceptable formulation may include a synthetic analog or derivative of a carotenoid. The subject may be administered a carotenoid analog or derivative, either alone or in combination with another carotenoid analog or derivative, or co-antioxidant formulation. The carotenoid analog may include a conjugated polyene with between 7 to 14 double bonds. The conjugated polyene may include a cyclic ring including at least one substituent. In some embodiments, a cyclic ring of a carotenoid analog or derivative may include at least one substituent. The substituent may be coupled to the cyclic ring with an ether functionality.