38304-91-5

Basic information

• Product Name: Minoxidil
• Synonyms: 2,4-diamino-6-piperidinopyrimidine3-n-oxide;4-pyrimidinediamine,6-(1-piperidinyl)-3-oxide;6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine;6-piperidino-2,4-diaminopyrimidine3-oxide;alopexil;alostil;lonolox;minossidile
• CAS NO: 38304-91-5
• Molecular Formula: C₉H₁₅N₅O
• Molecular Weight: 209.25
• EINECS: 253-874-2
• Product Categories: API;Intermediates & Fine Chemicals;Pharmaceuticals;API's;Potassium channel;Heteroctcles;Bases & Related Reagents;Nitric Oxide Reagents;Nucleotides;ROGAINE;Other APIs
• Mol File: 38304-91-5.mol

Chemical Properties

• Melting Point: 272-274 °C (dec.)(lit.)
• Boiling Point: 348.61°C (rough estimate)
• Flash Point: 166.5 °C
• Appearance: White crystalline powder
• Density: 1.1651 (rough estimate)
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.7610 (estimate)
• Storage Temp.: Store at RT
• Solubility: Slightly soluble in water, soluble in methanol and in propylene glycol.
• PKA: 4.61(at 25℃)
• Water Solubility: Soluble in water (2.2 mg/ml), 100% ethanol (29 mg/ml), propylene glycol, acetone, DMSO (6.5 mg/ml), and methanol.
• Stability: Stable for 2 years from date of purchase as supplied. Protect from moisture. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months.
• Merck: 14,6203
• CAS DataBase Reference: Minoxidil(CAS DataBase Reference)
• NIST Chemistry Reference: Minoxidil(38304-91-5)
• EPA Substance Registry System: Minoxidil(38304-91-5)

Safety Data

• Hazard Codes: Xn,T+
• Statements: 22-36/37/38-26/27/28
• Safety Statements: 26-36-45-36/37/39-22
• WGK Germany: 3
• RTECS: UV8200000
• Hazardous Substances Data: 38304-91-5(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Minoxidil is used as an antihypertensive agent for its ability to decrease arteriolar vascular resistance and lower blood pressure. It exerts its vasodilatory action by a direct effect on arteriolar smooth muscle and appears to have no effect on the CNS or the adrenergic nervous system in animals.
Minoxidil is also used as an antialopecia agent for its ability to activate ATP-activated K+ channels, promoting hair growth and treating hair loss.
Used in Hair Care Industry:
Minoxidil is used as a hair growth promoter for its ability to stimulate hair follicles and improve hair density. It is commonly found in over-the-counter hair loss treatments, such as Rogaine (Pharmacia & Upjohn) and Minodyl (Quantum Pharmics), to help slow down hair loss and promote hair regrowth in both men and women.

an antihypertensive vasodilator medication

Minoxidil is an antihypertensive vasodilator medication also claiming to slow or stop hair loss and promote hair regrowth. It is available over the counter for treatment of androgenic alopecia, among other baldness treatments, but measurable changes, if experienced, disappear within months after discontinuation of treatment.Minoxidil was first sold as a drug for high blood pressure and was noted to have the interesting side-effect of increased body hair-growth, or in some cases, significant hair loss. Treatments for baldness and hair loss usually include a 5% concentration solution that is designed for men, whereas the 2% concentration solutions are designed for women.

Indications and Usage

Minoxidil is a type of oral drug that is clinically used to lower blood pressure, and it is also called Loniten and piperidine diamine. Minoxidil is an antihypertensive drug that is clinically used to treat intractable, primary or renal hypertension. It can also be used to treat severe hypertension that does not respond well to other antihypertensive drugs, but it needs to be used in combination with diuretic drugs to prevent water and sodium retention, and combined use with beta receptor blockers may increase its curative effects and reduce adverse effects. Minoxidil is also used to prevent grease-type alopecia and on livestock.

Mechanisms of Action

Minoxidil is a type of potassium channel opener and can directly relax smooth vascular muscles and has a strong small artery dilating effect. It can reduce peripheral resistance, dilate blood vessels, and lower blood pressure while having no effect on blood volume, thus promoting venous return. In addition, due to reflective regulation and positive frequency effects, it can increase cardiac output and heart rate, but will not cause orthostatic hypotension.

Adverse reactions

Long term use of Minoxidil may have the side effect of increased body hair, such as arm hair. Adverse reactions to oral intake mainly include: weight gain and lower body swelling due to water and sodium retention, heart palpitations and arrhythmia due to reflexive sympathetic nervous excitement, and hirsuitism. Adverse reactions to external use mainly include: skin irritation, red spots in applied areas, itching, and other skin inflammation reactions. Although only a small amount is absorbed, but there is also a slight possibility of causing a recurrence in patients with a history or heart disease. Use with caution if suffering from cerebrovascular disease, non-hypertensive heart failure, coronary heart disease, angina pectoris, myocardial infarction, pericardial effusion, renal dysfunction and other diseases.

Contradictions

Do not use if allergic to Minoxidil or suffering from pheochromocytoma.

Originator

Loniten ,Upjohn ,US ,1979

Manufacturing Process

Barbituric acid is reacted with phosphorus oxychloride then with 2,4,6-trichloropyrimidine and that product with ammonia to give 4-chloro-2,6-diaminopyritnidine.A 30 g (0.15 mol) quantity of 4-chloro-2,6-diaminopyrimidine is dissolved in600 ml of hot 3A alcohol, the solution cooled to 0°C to 10°C and 41.8 g (0.24mol) of m-chloroperbenzoic acid is added. The mixture is held at 0°C to 10°Cfor 4 hours and filtered. The solid is shaken for 2 hours in 0.24 mol of 10%sodium hydroxide and filtered. The solid is washed with water and dried toyield 193 g of crude product. This product is extracted for 1 hour with 900 mlof boiling acetonitrile to yield 14.8 g (44.7% yield) of 6-amino-4-chloro-1,2-dihydro-1-hydroxy-2-iminopyrimidine, melting point 193°C.A mixture of 3.0 g (0.019 mol) of 6-amino-4-chloro-1,2-dihydro-1-hydroxy-2-iminopyrimidine and 35 ml of piperidine is refluxed for 1.5 hours, cooled andfiltered. The solid is shaken for 20 minutes in a solution of 0.8 g of sodiumhydroxide in 30 ml of water and filtered. The solid is washed with water andextracted with 800 ml of boiling acetonitrile and filtered to yield 3.5 g (89%)yield of 6-amino-4-chloro-1,2-dihydro-1-hydroxy-2-iminopyrimidine, meltingpoint 248°C, decomposition at 259°C to 261°C.

Therapeutic Function

Antihypertensive

Biological Activity

Antihypertensive. Antialopecia agent. K + channel (K ATP ) activator.

Biochem/physiol Actions

Activates ATP-activated K+ channels; vasodilator; slow or stop hair loss and promote hair regrowth.

Mechanism of action

Potassium channel openers are drugs that activate (i.e., open) ATP-sensitive K+ channels in the VSM. By opening these potassium channels, there is increased efflux of potassium ions from the cells, causing hyperpolarization of VSM, which closes the voltage-gated calcium channels and, thereby, decreases intracellular calcium. With less calcium available to combine with calmodulin, there is less activation of MLCK and phosphorylation of myosin light chains. This leads to relaxation and vasodilation. Because small arteries and arterioles normally have a high degree of smooth muscle tone, these drugs are particularly effective in dilating these resistance vessels, decreasing systemic vascular resistance, and lowering arterial pressure. The fall in arterial pressure leads to reflex cardiac stimulation (baroreceptor-mediated tachycardia). Minoxidil, as its active metabolite minoxidil O-sulfate, prolongs the opening of the potassium channel, sustaining greater vasodilation on arterioles than on veins. The drug decreases blood pressure in both the supine and standing positions, and there is no orthostatic hypotension. Associated with the decrease in peripheral resistance and blood pressure is a reflex response that is accompanied by increased heart rate, cardiac output, and stroke volume, which can be attenuated by the coadministration of a β-blocker. Along with this decrease in peripheral resistance is increased plasma renin activity and sodium and water retention, which can result in expansion of fluid volume, edema, and congestive heart failure. The sodium- and water-retaining effects of minoxidil can be reversed by coadministration of a diuretic. When minoxidil is used in conjunction with a β-adrenergic blocker, pulmonary artery pressure remains essentially unchanged.

Pharmacokinetics

Minoxidil is absorbed from the GI tract and is metabolized to its active sulfate metabolite. Plasma concentrations for minoxidil sulfate peak within 1 hour and then decline rapidly. Following an oral dose of minoxidil, its hypotensive effect begins in 30 minutes, is maximal in 2 to 8 hours, and persists for approximately 2 to 5 days. The delayed onset of the hypotensive effect for minoxidil is attributed to its metabolism to its active metabolite. The drug is not bound to plasma proteins. The major metabolite for minoxidil is its N-O-glucuronide, which unlike the sulfate metabolite is inactive as a hypotensive agent. Approximately 10 to 20% of an oral dose of minoxidil is metabolized to its active metabolite, minoxidil O-sulfate, and approximately 20% of minoxidil is excreted unchanged.

Clinical Use

Minoxidil is used for severe hypertension that is difficultto control with other antihypertensive agents. The drug hassome of the characteristic side effects of direct vasodilatorydrugs. It causes sodium and water retention and may requirecoadministration of a diuretic. Minoxidil also causes reflextachycardia, which can be controlled by use of a -adrenergicblocking agent.Minoxidil topical solution is used to treat alopecia androgenitica(male-pattern baldness). Although the mechanismis not clearly understood, topical minoxidil is believed to increasecutaneous blood flow, which may stimulate hairgrowth. The stimulation of hair growth is attributed to vasodilationin the vicinity of application of the drug, resultingin better nourishment of the local hair follicles.

Side effects

Adverse reactions include local irritation and contact dermatitis. If the treatment is discontinued, clinical regression occurs within 3 months to the state of hair thinning that would have occurred had the treatment not been started. Twice-daily treatment is more efficacious than once-daily application. Women who use the5%concentrationmay note the development of facial hair, which is reversible on discontinuation of the medication. The 5% concentration can be more irritating than the 2% solution.

Synthesis

Minoxidil, 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine (22.8.5), is synthesized from barbituric acid, the reaction of which with phosphorous oxychloride gives 2,4,6-trichloropyrimidine (22.8.1). Upon reaction with ammonium, this turns into 2,4-diamino-6-chloropyrimidine (22.8.2). Next, the resulting 2,4-diamino-6- chloropyrimidine (22.8.2) undergoes reaction with 2,4-dichlorophenol in the presence of potassium hydroxide, giving 2,4-diamino-6-(2,4-dichlorophenoxy)-pyrimidine (22.8.3). Oxidation of this product with 3-chloroperbenzoic acid gives 2,4-diamino-6-(2,4- dichlorophenoxy)pyrimidine-3-oxide (22.8.4), the 2,4-dichlorophenoxyl group of which is replaced with a piperidine group at high temperature, giving minoxidil (22.8.5).

Drug interactions

When minoxidil is administered with diuretics or other hypotensive drugs, the hypotensive effect of minoxidil increases, and concurrent use may cause profound orthostatic hypotensive effects.

Metabolism

Extensively metabolised by the liver. It requires sulphation to become active, but the major metabolite is a glucuronide conjugate. Excreted mainly in the urine in the form of metabolites. Minoxidil and its metabolites are dialysable, although the pharmacological effect is not reversed.

References

1) Meisheri et al. (1988), Mechanism of action of minoxidil sulfate-induced vasodilation: a role for increased K+ permeability; J. Pharmacol. Exp. Ther., 245 7 2) Messenger and Rundegren (2004) Minoxidil:mechanisms of action on hair growth; Br. J. Dermatol., 150 186

InChI:InChI=1/C9H15N5O/c10-7-6-8(12-9(11)14(7)15)13-4-2-1-3-5-13/h6H,1-5,10H2,(H2,11,12)

Synthetic route

2,6-diamino-4-chloro-pyrimidine N-oxide (35139-67-4) → 2,4-diamino-6-piperidinopyrimidine 3-oxide (38304-91-5)

Conditions	Yield
at 106℃; for 2h;	80%

piperidine (110-89-4) + 2,6-diamino-4-chloro-pyrimidine N-oxide (35139-67-4) → 2,4-diamino-6-piperidinopyrimidine 3-oxide (38304-91-5)

Conditions	Yield
In dimethyl sulfoxide at 80℃; Rate constant; Thermodynamic data; various temp.; ΔH*, ΔS*;

ketoconazole (65277-42-1) → 2,4-diamino-6-piperidinopyrimidine 3-oxide (38304-91-5)

Upstream product

• 110-89-4 piperidine 
• 35139-67-4 2,6-diamino-4-chloro-pyrimidine N-oxide 
• 65277-42-1 ketoconazole 

Relevant articles and documents

The promoted synthesis of minoxidil by magnetic nanoparticles of cobalt ferrite (CoFe2O4) as a heterogeneous reusable catalyst

Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) was primarily recognized as a drug for reducing vascular resistance to blood flow. It was later introduced as a more important medicine for topical stimulation of hair growth and baldness reverting as well as treatment of androgenic alopecia through increasing prostaglandin endoperoxide synthesis. In this study, magnetic nanoparticles (MNPs) of spinel ferrites (MFe 2 O 4, M = Co, Ni, Fe, Cu, and Zn) via solid-state grinding procedure were prepared and then characterized using X-ray diffraction, scanning electron microscopy, transmission electron microscopy, vibrating sample magnetometer, and Fourier transform infrared techniques. The prepared nanoferrites were utilized as efficient and green heterogeneous catalysts for N -oxidation of 2,6-diamino-4-chloro-pyrimidine with H 2 O 2 in refluxing ethanol giving 2,6-diamino-4-chloro-pyrimidine N -oxide as a starting material for the synthesis of 2,4-diamino-6-piperidinopyrimidine 3-oxide (minoxidil). Among the examined nanoferrites, CoFe 2 O 4 MNPs exhibited prominent catalytic activity giving the product in 95% yield within 60 min. Moreover, the reusability of nano-CoFe 2 O 4 was examined for 6 consecutive cycles without significant loss of catalytic activity and magnetic property.

METHOD OF ENHANCING HAIR GROWTH

Methods and compositions for stimulating the growth of hair are disclosed wherein said compositions include bimatoprost and minoxidil in a vehicle for topical application to the skin of a mammal, e.g. a human, whereby the combination of bimatoprost and minoxidil produces a faster onset of hair growth in humans or other mammals and wherein said composition brings about a synergestic result of faster onset of hair growth as compared to compositions comprising bimatoprost and minoxidil, alone.

Nanoparticles comprising half esters of poly (methyl vinyl ether-co-maleic anhydride) and uses thereof

The present invention relates to nanoparticles for encapsulating compounds, the preparation and uses thereof, said nanoparticles being based on half (C1-C4) alkyl esters of poly (methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymers. Said nanoparticles can encapsulate or incorporate a product of interest. For use in the agricultural, cosmetic, food or pharmaceutical fields.

3-deoxyglucosone and skin

The invention relates to a method of removing 3-deoxyglucosone and other alpha-dicarbonyl sugars from skin. The invention further relates to methods of inhibiting production and function of 3-deoxyglucosone and other alpha-dicarbonyl sugars in skin. The invention also relates to methods of treating 3-deoxyglucosone and other alpha-dicarbonyl sugars associated diseases and disorders of skin.

Scalp life conditioner

The present invention is an improved scalp conditioner for conditions related to flaky and inflamed scalp that are commonly associated with dandruff, seborrhea, psoriasis and burns from the use of alkaline based products. The method involves administering the product to the scalp of the head and gently massaging the scalp. It can be administered several times per week.

Topical delivery systems for active agents

This invention relates to a method for enhancing the transmembrane penetration of benefit agents using a certain non-ionic lipid/surfactant-containing formulation as an enhancing agent, and the compositions used therein. Various active agents, such as anti-dandruff agents, hair growth agents, hair inhibitor agents, anti-acne agents, anti-aging agents, depilatory agents, and depigmentation agents, may be effectively delivered into the skin, hair follicles and sebaceous glands using the compositions of the present invention.

Relative Reactivity in Piperidino-Dechlorination of 2,4-Diamino-6-chloropyrimidine, 2,4-Diamino-6-chloropyrimidine N(3)-Oxide, and Their Acetylamino Analogues

The second-order rate constants kA for the piperidino-dechlorination of 2,4-diamino-6-chloropyrimidine (1a), 2,4-bis(acetylamino)-6-chloropyrimidine (1b), 2,4-diamino-6-chloropyrimidine N(3)-oxide (2a), and 2,4-bis(acetylamino)-6-chloropyrimidine N(3)-oxide (2b) have been determined from the corresponding pseudo-first-order rate constants, kψ, measured in DMSO at 21.0 deg C by the UV spectrophotometric procedure.The second-order rate coefficients of the less reactive substrates 1a and 2a at 21 deg C have been obtained as extrapolated values from Arrhenius plots of kA values, calculated through the psudo-first-order-type relationship, kψ = kA(where is the amine concentration),from the kψ measured at higher temperatures (kA(1a) = 1.36E-5 and kA(2a) = 3.44E-5 L mol-1 min -1).The reactivities of the acyl derivatives 1b and 2b are remarkably higher than that of the parent compounds 1a and 2a.The pseudo-first-order-rate constants of the more reactive substrates 1b and 2b, measured as a function of piperidine concentration, increase linearly for 1b, with a decreasing curvilinear slope only in the higher concentration region of base; in contrast, the reactivity of 2b remains almost constant and lower than that of 1b for most of the employed base concentrations.This behavior is due to the acidic character of compound 2b, which is almost totally transformed by excess piperidine into an anionic form, much less reactive than the protonated one toward the nucleophilic attack, even at relatively low base concentrations.Compound 1b is much less acidic than 2b and shows deviations from the second-order-type linear behavior only for the higher base concentrations.The equilibrium constant for the acid-base reaction of 2b with piperidine has been obtained spectrophotometrically (K= 0.007 +/- 0.001), and the second-order rate coefficient kA has been calculated from the constant apparent reactivity kψ by means of the formula kA = kψ/K (where is the piperidinium ion concentration) (kA(2b) = 2.7 L mol-1 min-1).That of 1b is given by the slope of the experimental curve kψ vs in the proximity of the origin (kA(1b) = 0.15 L mol-1 min-1).The results indicate that both the acetylation of the exocyclic -NH2 groups and the oxidation of the cyclic N(3)-atom increase the reactivity of the parent compounds toward piperidinolysis, but that the first modification is much more effective than the second one.The dependence of kψ of 1b and 2b on the amine concentration does not give any evidence for base catalysis, as expected in the model of the intermediate complex mechanism when the leaving group is fast to separate (as the -Cl group is) and/or the complex formation is rate-limiting.

Minoxidil gel

The present invention provides a novel pharmaceutically acceptable gel containing minoxidil for topical application.

Cosmetic composition comprising an ester of pyroglutamic acid

A preserved composition suitable for topical application to mammalian skin or hair for inducing, maintaining or increasing hair growth comprises: (i) a special ester of pyroglutamic acid; and (ii) a cosmetically acceptable vehicle for the ester.

Amino-substituted pyrimidines, derivatives and methods of use therefor

The present invention relates to compositions and methods for inhibiting nonenzymatic cross-linking (protein aging). Accordingly, a composition is disclosed which comprises an agent capable of inhibiting the formation of advanced glycosylation end products of target proteins by reacting with the carbonyl moiety of the early glycosylation product of such target proteins formed by their initial glycosylation. The method comprises contacting the target protein with the composition. Both industrial and therapeutic applications for the invention are envisioned, as food spoilage and animal protein aging can be treated.