154992-24-2

Basic information

• Product Name: RU 58841
• Synonyms: RU 58841;4-(4,4-Dimethyl-2,5-dioxo-3-(4-hydroxybutyl)1-imidazolidinyl)-2-(trifluoromethyl)benzonitrile;4-[3-(4-Hydroxybutyl)-4,4-dimethyl-2,5-dioxo-1-imidazolidinyl]-2-(trifluoromethyl)benzonitrile;4-[3-(4-Hydroxybutyl)-4,4-diMethyl-2,5-dioxoiMidazolidin-1-yl]-2-(trifluoroMethyl)benzonitrile;Benzonitrile, 4-[3-(4-hydroxybutyl)-4,4-diMethyl-2,5-dioxo-1-iMidazolidinyl]-2-(trifluoroMethyl)-;RU 58841(RU-58841);4-[3-(4-Hydroxybutyl)-4,4-dimethyl-2,5-dioxo-1-imidazolidinyl]-2-(trifluoromethyl)benzonitrile RU 58841;RU 5884
• CAS NO: 154992-24-2
• Molecular Formula: C₁₇H₁₈F₃N₃O₃
• Molecular Weight: 369.341
• EINECS: 1592732-453-0
• Product Categories: Inhibitors
• Mol File: 154992-24-2.mol

Chemical Properties

• Boiling Point: 493.588 °C at 760 mmHg
• Flash Point: 252.313 °C
• Appearance: /
• Density: 1.39
• Vapor Pressure: 1.47E-10mmHg at 25°C
• Refractive Index: 1.559
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• PKA: 15.09±0.10(Predicted)
• CAS DataBase Reference: RU 58841(CAS DataBase Reference)
• NIST Chemistry Reference: RU 58841(154992-24-2)
• EPA Substance Registry System: RU 58841(154992-24-2)

Safety Data

• Hazardous Substances Data: 154992-24-2(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
RU 58841 is used as a hair growth agent for promoting hair growth on the scalp and retarding hair growth of both beard and body hair follicles. Its efficacy has been demonstrated in stumptailed macaques, a model for male pattern baldness.
Used in Hair Loss Treatment:
RU 58841 is used as a non-steroidal antiandrogenic medication for avoiding hair loss, particularly in the context of acne and androgenetic alopecia (male pattern baldness). It has shown potential in modulating hair growth and may be used in combination with other treatments, such as minoxidil, to enhance its effects.
Used in Research and Development:
RU 58841 serves as a specific androgen receptor antagonist or anti-androgen in various research applications, providing insights into the mechanisms of androgen action and the development of novel treatments for androgen-related conditions.

Androgen receptor

RU 58841 (PSK-3841) is a specific androgen receptor antagonist or anti-androgen. RU 58841 (PSK-3841) has a dramatic effect on hair regrowth. Androgen receptor (AR) is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus. Upon binding the hormone ligand, the receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive genes. The androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor. The main function of the androgen receptor is as a DNA-binding transcription factor that regulates gene expression. Androgen regulated genes are critical for the development and maintenance of the male sexual phenotype. Mutations in this gene are also associated with complete androgen insensitivity (CAIS).

Laboratory Procedures

RU-58841 is supplied as a crystalline solid. A stock solution may be made by dissolving the RU-58841 in the solvent of choice. RU-58841 is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide (DMF), which should be purged with an inert gas. The solubility of RU-58841 is approximately33 mg/ml in ethanol and DMF and approximately 25 mg/ml in DMSO. RU-58841 is sparingly soluble in aqueous buffers. For maximum solubility in aqueous buffers, RU-58841 should first be dissolved in ethanol and then diluted with the aqueous buffer of choice. RU-58841 has a solubility of approximately 0.16 mg/ml in a 1:5 solution of ethanol:PBS (pH 7.2) using this method. We do not recommend storing the aqueous solution for more than one day.

Side effects

Since RU58841 has not passed into phase two of drug development, there are literally no studies that have highlighted the side effects of this medication specifically. Pharmacologically speaking, there are absolutely no pharmacologic products that are 100% free of side effects. Like with every medication, RU58841 also affects each individual differently. But based on the physiologic processes it undergoes, we can hypothesize on some of its potential side effects. For instance, you should be aware that RU58841 does not only block DHT but all other androgens including testosterone.

References

Battmann, T., Bonfils, A., Branche, C., et al. RU 58841, a new specific topical antiandrogen: A candidate of choice for the treatment of acne, androgenetic alopecia and hirsutism. J. Steroid Biochem. Mol. Biol. 48(1), 55-60 (1994). Obana, N., Chang, C., and Uno, H. Inhibition of hair growth by testosterone in the presence of dermal papilla cells from the frontal bald scalp of the postpubertal stumptailed macaque. Endocrinology138(1), 356-361 (1997).

Preparation

RU58841 is active against baldness and is commercially available. The previously reported synthesis uses phosgene, three discrete inert atmosphere steps and three steps that require flash chromatography. Our synthesis uses no phosgene, only one inert atmosphere step and does not require flash chromatography. Alternative synthesis of the anti-baldness compound RU58841

Synthesis Reference(s)

A bromine–nitro substitution at tertiary carbon and using 2-nitropropane as leaving group enable a short phosgene-free synthesis of RU58841.pubs.rsc.org

InChI:InChI=1/C17H18F3N3O3/c1-16(2)14(25)23(15(26)22(16)7-3-4-8-24)12-6-5-11(10-21)13(9-12)17(18,19)20/h5-6,9,24H,3-4,7-8H2,1-2H3

Synthetic route

4-Bromobutyl acetate (4753-59-7) + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → 4-[3-(4-hydroxybutyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (154992-24-2)

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.25h; Stage #2: 4-Bromobutyl acetate In N,N-dimethyl-formamide; mineral oil at 50℃; for 2h;	80%

toluene ethanol + 4-Bromobutyl acetate (4753-59-7) + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → 4-[3-(4-hydroxybutyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (154992-24-2)

Conditions	Yield
In N-methyl-acetamide; methanol; ethanol; dichloromethane; water

4-amino-2-trifluoromethylbenzonitrile (654-70-6) → 4-[3-(4-hydroxybutyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (154992-24-2)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: potassium carbonate / 1,2-dichloro-ethane / 14 h / 20 °C 2.1: sodium nitrite / N,N-dimethyl-formamide / 14 h / 20 °C 3.1: iron; hydrogenchloride / isopropyl alcohol; ethanol; water / 1 h / 90 °C 4.1: potassium carbonate / 1,2-dichloro-ethane / 14 h 5.1: sodium nitrite / N,N-dimethyl-formamide / 14 h / 20 °C 6.1: N,N-dimethyl-formamide / 7 h / 110 °C 7.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.25 h 7.2: 2 h / 50 °C View Scheme

2-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropanamide (1259327-69-9) → 4-[3-(4-hydroxybutyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (154992-24-2)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: sodium nitrite / N,N-dimethyl-formamide / 14 h / 20 °C 2.1: iron; hydrogenchloride / isopropyl alcohol; ethanol; water / 1 h / 90 °C 3.1: potassium carbonate / 1,2-dichloro-ethane / 14 h 4.1: sodium nitrite / N,N-dimethyl-formamide / 14 h / 20 °C 5.1: N,N-dimethyl-formamide / 7 h / 110 °C 6.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.25 h 6.2: 2 h / 50 °C View Scheme

N-[4-cyano-3-(tri-fluoromethyl)phenyl]-2-methyl-2-nitropropanamide → 4-[3-(4-hydroxybutyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (154992-24-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: iron; hydrogenchloride / isopropyl alcohol; ethanol; water / 1 h / 90 °C 2.1: potassium carbonate / 1,2-dichloro-ethane / 14 h 3.1: sodium nitrite / N,N-dimethyl-formamide / 14 h / 20 °C 4.1: N,N-dimethyl-formamide / 7 h / 110 °C 5.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.25 h 5.2: 2 h / 50 °C View Scheme

2-amino-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methylpropanamide (208122-09-2) → 4-[3-(4-hydroxybutyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (154992-24-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium carbonate / 1,2-dichloro-ethane / 14 h 2.1: sodium nitrite / N,N-dimethyl-formamide / 14 h / 20 °C 3.1: N,N-dimethyl-formamide / 7 h / 110 °C 4.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.25 h 4.2: 2 h / 50 °C View Scheme

2-bromo-N-(1-{[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl}-1-methylethyl)-2-methylpropanamide → 4-[3-(4-hydroxybutyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (154992-24-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium nitrite / N,N-dimethyl-formamide / 14 h / 20 °C 2.1: N,N-dimethyl-formamide / 7 h / 110 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.25 h 3.2: 2 h / 50 °C View Scheme

tetradecanoyl chloride (112-64-1) + 4-[3-(4-hydroxybutyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (154992-24-2) → RU 58841-myristate

Conditions	Yield
With triethylamine In chloroform for 24h;	55.2%

1H-imidazole (288-32-4) + sodium thiosulfate + triphenylphosphine (603-35-0) + 4-[3-(4-hydroxybutyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (154992-24-2) → 4-(4,4-dimethyl-2,5-dioxo-3-(4-iodobutyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile (192805-64-4)

Conditions	Yield
With iodine In dichloromethane

water+ice + isopropyl chloroformate (108-23-6) + 4-[3-(4-hydroxybutyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (154992-24-2) → bis-2-propyl carbonate (6482-34-4)

Conditions	Yield
With 2-(Dimethylamino)pyridine; sodium chloride In pyridine; toluene

4-[3-(4-hydroxybutyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (154992-24-2) + cyclohexyl chloroformate (13248-54-9) → dicyclohexyl carbonate (4427-97-8)

Conditions	Yield
With pyridine; dmap

Upstream product

• 4753-59-7 4-Bromobutyl acetate 
• 143782-20-1 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 
• 654-70-6 4-amino-2-trifluoromethylbenzonitrile 
• 1259327-69-9 2-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropanamide 
• 208122-09-2 2-amino-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methylpropanamide 

Downstream Products

• 192805-64-4 4-(4,4-dimethyl-2,5-dioxo-3-(4-iodobutyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile 
• 6482-34-4 bis-2-propyl carbonate 
• 4427-97-8 dicyclohexyl carbonate 

Relevant articles and documents

Alternative synthesis of the anti-baldness compound RU58841

RU58841 is active against baldness and is commercially available. The previously reported synthesis uses phosgene, three discrete inert atmosphere steps and three steps that require flash chromatography. Our synthesis uses no phosgene, only one inert atmosphere step and does not require flash chromatography. This is achieved by stepwise construction of the hydantoin moiety around the amino group of 3-trifluoromethyl-4-cyanoaniline and ring closure to give a 2-nitropropane leaving group. On a small scale we achieved an overall yield of 33%.

Cosmetic or pharmaceutical compositions

A cosmetic or pharmaceutical composition containing a dermatologically effective amount of at least one liposome containing a compound of the formula

Phenylimidazolidine preparation process

A subject of the invention is a preparation process for the products of formula (I): STR1 in which R1 and R2 represent in particular hydrogen, cyano, halogen or amino,R3 represents in particular hydrogen or hydroxyl alkyl, R4 and R5 represent in particular optionally substituted alkyl, X and y represent oxygen or sulphur, characterized in that a product of formula (A): STR2 is prepared in which W represents a halogen atom or a hydantoin derivative, which is subjected to various reactions in order to obtain the products of formula (I), all their isomers and their salts.