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Itraconazole structure
Itraconazole structure

Itraconazole

Iupac Name:2-butan-2-yl-4-[4-[4-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one
CAS No.: 84625-61-6
Molecular Weight:705.641
Modify Date.: 2022-03-12 02:23
Introduction: Itraconazole is an orally-active triazole antifungal indicated for use in the treatment ofdermal, vaginal and systemic mycoses. In immunocompromised and AIDS patients,itraconazole has been shown to significantly reduce the incidence of relapses ofcryptococcal meningitis. View more+
1. Names and Identifiers
1.1 Name
Itraconazole
1.2 Synonyms

)-1-sec-Butyl-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-d2-1,2,4-triazolin-5-one -1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)-1-piperazinyl)phenyl)-2,4-dihyd 2-(butan-2-yl)-4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one 2-(Butan-2-yl)-4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorphenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-on 2-sec-Butyl-4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)-1-piperazinyl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one 2-sec-Butyl-4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one 3H-1,2,4-Triazol-3-one, 4-[4-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)- 3h-1,2,4-triazol-3-one,4-(4-(4-(4-((2-(2,4-dichlorophenyl)-2-(1h-1,2,4-triazol 4-(4-{4-[4-({[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl}oxy)phenyl]piperazin-1-yl}phenyl)-2-(1-methylpropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-2-(1-methylpropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 4-{4-[4-(4-{[(2R,4S)-2-(2,4-Dichlorphenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-2-(1-methylpropyl)-2,4-dihydro-3H-1,2,4-triazol-3-on Candistat Canditral Cladosal 100 Itrac ITRACONAZOLE-D3 Itrizole MFCD08064196 ORICONAZOLE R51211 Sporanos SPORANOX TRIASPORIN

1.3 CAS No.
84625-61-6
1.4 CID
3793
1.5 EINECS(EC#)
617-596-9
1.6 Molecular Formula
C35H38Cl2N8O4 (isomer)
1.7 Inchi
InChI=1S/C35H38Cl2N8O4/c1-3-25(2)45-34(46)44(24-40-45)29-7-5-27(6-8-29)41-14-16-42(17-15-41)28-9-11-30(12-10-28)47-19-31-20-48-35(49-31,21-43-23-38-22-39-43)32-13-4-26(36)18-33(32)37/h4-13,18,22-25,31H,3,14-17,19-21H2,1-2H3
1.8 InChkey
VHVPQPYKVGDNFY-UHFFFAOYSA-N
1.9 Canonical Smiles
CCC(C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OCC5COC(O5)(CN6C=NC=N6)C7=C(C=C(C=C7)Cl)Cl
1.10 Isomers Smiles
CCC(C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OCC5COC(O5)(CN6C=NC=N6)C7=C(C=C(C=C7)Cl)Cl
2. Properties
3.1 Density
1.4
3.1 Melting point
166℃
3.1 Boiling point
850 oC at 760 mmHg
3.1 Refractive index
1.678
3.1 Flash Point
467.9 oC
3.1 Vapour pressure
2.6X10-20 mm Hg at 25 deg C (est)
3.1 Precise Quality
704.23900
3.1 PSA
104.70000
3.1 logP
5.70730
3.1 Solubility
chloroform: 50?mg/mL, clear, colorless
3.2 Appearance
off-White crystalline solid
3.3 Storage
Keep Cold.
3.4 Chemical Properties
It is crystallized from toluene with the melting point of 166.2 °C and PKa of 3.7. It is almost insoluble in water and the dilute acid solution. Acute toxicity LD50 (14 days) mice, rats, dogs (mg/kg):> 320,> 320,> 200 orally.
3.5 Color/Form
Solid
3.6 pKa
3.7(at 25℃)
3.7 Water Solubility
chloroform: 50?mg/mL, clear, colorless
3.8 Stability
Stable. Incompatible with strong oxidizing agents.
3.9 StorageTemp
2-8°C
3. Use and Manufacturing
4.1 GHS Classification
Signal: Warning
GHS Hazard Statements
Aggregated GHS information provided by 39 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]
H315 (76.92%): Causes skin irritation [Warning Skin corrosion/irritation]
H319 (76.92%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]
H335 (74.36%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

Precautionary Statement Codes
P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501
4.2 Usage
The imidazole antifungal agents for the triazole ring, through inhibiting the activation of cytochrome P-450, including oxidase and peroxidase, disable the 14, α-methyl sterols to be dehydrogenated and be converted to ergosterol, so that the growth and proliferation of fungi are inhibited. They have strong lipophilicity and penetrate through the biofilm to inhibit the binding of the membrane to the fungus. The antibacterial spectrum is similar to ketoconazole. It is effective in the treatment of superficial fungal diseases such as vaginal and oral candidiasis as well as skin mycosis. Furthermore, it is expected to become the highly-efficient and safe drugs for the treatment of deep fungal infections such as cryptococcal encephalitis (AIDS). It is used for the treatment of vulvovaginal candidiasis, pityriasis and skin fungal disease pityriasis caused by sensitive fungi.It can be used for the synthesis of broad-spectrum azole antifungal agents for the treatment of systemic infection caused by deep fungus. It can also be used for the treatment of candidiasis and aspergillosis.
4. Safety and Handling
5.1 Symbol
GHS07
5.1 Hazard Codes
Xi
5.1 Signal Word
Warning
5.1 Risk Statements
R36/37/38
5.1 Safety Statements
S22;S26;S36
5.1 Hazard Declaration
H302-H315-H319-H335
5.1 RIDADR
NONH for all modes of transport
5.1 Caution Statement
P261-P305 + P351 + P338
5.1 WGK Germany
3
5.1 RTECS
XZ5481000
5.1 Safety

Hazard Codes:?IrritantXi,HarmfulXn
Risk Statements: 36/37/38-36/38-22?
R36/37/38: Irritating to eyes, respiratory system and skin.?
R36/38: Irritating to eyes and skin.?
R22: Harmful if swallowed.
Safety Statements: 22-26-36?
S22: Do not breathe dust.?
S26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.?
S36: Wear suitable protective clothing.
WGK Germany: 3
RTECS Itraconazole (CAS NO.84625-61-6): XZ5481000

5.2 Specification

?Itraconazole (CAS NO.84625-61-6), its Synonyms are (+-)-1-sec-Butyl-4-(p-(4-(p-(((2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)-1-piperazinyl)phenyl)-delta(sup 2)-1,2,4-triazolin-5-one ; Hyphanox ; Itraconazol ; Itraconazolum ; Oriconazole ; 3H-1,2,4-Triazol-3-one, 4-(4-(4-(4-((2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)-1-piperazinyl)phenyl)-2,4-dihydro-2-(1-methylpropyl)- . It is an off-white crystalline solid.

5.3 Toxicity

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
dog LD50 oral > 200mg/kg (200mg/kg) ? Reviews of Infectious Diseases. Vol. 9(Suppl,
guinea pig LD50 oral > 160mg/kg (160mg/kg) ? Reviews of Infectious Diseases. Vol. 9(Suppl,
man TDLo oral 240mg/kg/6W-I (240mg/kg) LIVER: "JAUNDICE, OTHER OR UNCLASSIFIED"

LIVER: LIVER FUNCTION TESTS IMPAIRED
Lancet. Vol. 340, Pg. 251, 1992.
mouse LD50 intravenous 46400ug/kg (46.4mg/kg) ? Kiso to Rinsho. Clinical Report. Vol. 25, Pg. 381, 1991.
mouse LD50 oral > 320mg/kg (320mg/kg) ? Reviews of Infectious Diseases. Vol. 9(Suppl,
rat LD50 intravenous 40mg/kg (40mg/kg) ? Kiso to Rinsho. Clinical Report. Vol. 25, Pg. 381, 1991.
rat LD50 oral > 320mg/kg (320mg/kg) ? Reviews of Infectious Diseases. Vol. 9(Suppl,
women TDLo oral 32mg/kg/8D-I (32mg/kg) SKIN AND APPENDAGES (SKIN): HAIR: OTHER British Medical Journal. Vol. 293, Pg. 822, 1986.
women TDLo oral 140mg/kg/5W-I (140mg/kg) LIVER: "JAUNDICE, OTHER OR UNCLASSIFIED"

LIVER: LIVER FUNCTION TESTS IMPAIRED

SKIN AND APPENDAGES (SKIN): "DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE"
Lancet. Vol. 340, Pg. 251, 1992.

5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Acute toxicity - Oral, Category 4

Skin irritation, Category 2

Eye irritation, Category 2

Specific target organ toxicity \u2013 single exposure, Category 3

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word

Warning

Hazard statement(s)

H302 Harmful if swallowed

H315 Causes skin irritation

H319 Causes serious eye irritation

H335 May cause respiratory irritation

Precautionary statement(s)
Prevention

P264 Wash ... thoroughly after handling.

P270 Do not eat, drink or smoke when using this product.

P280 Wear protective gloves/protective clothing/eye protection/face protection.

P261 Avoid breathing dust/fume/gas/mist/vapours/spray.

P271 Use only outdoors or in a well-ventilated area.

Response

P301+P312 IF SWALLOWED: Call a POISON CENTER/doctor/\u2026if you feel unwell.

P330 Rinse mouth.

P302+P352 IF ON SKIN: Wash with plenty of water/...

P321 Specific treatment (see ... on this label).

P332+P313 If skin irritation occurs: Get medical advice/attention.

P362+P364 Take off contaminated clothing and wash it before reuse.

P305+P351+P338 IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.

P337+P313 If eye irritation persists: Get medical advice/attention.

P304+P340 IF INHALED: Remove person to fresh air and keep comfortable for breathing.

P312 Call a POISON CENTER/doctor/\u2026if you feel unwell.

Storage

P403+P233 Store in a well-ventilated place. Keep container tightly closed.

P405 Store locked up.

Disposal

P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

7. Precursor and Product
8. Other Information
8.0 Merck
14,5245
8.1 Broad - spectrum antifungal agents
Itraconazole is an artificially synthetic clotrimazole, being a broad-spectrum synthetic antifungal agent. Its antimicrobial spectrum and antimicrobial mechanism is similar to clotrimazole, but has strong antibacterial activity against Aspergillus. It exerts its anti-fungal effect through changing the fungal cell membrane permeability with antibacterial activity against superficial and deep fungal pathogens. Its antibacterial spectrum is broader and stronger than ketoconazole, being able to inhibit the ergosterol synthesis of fungal cell membrane, thus playing the antifungal effect. This product is suitable for the treatment of Dermatophytes (Trichophyton, Microsporum, Flocculent Epidermophyton), Yeast [Cryptococcus neoformans, Pityrosporum, Candida (including Candida albicans, Candida glabrata and candida krusei)], Aspergillus, Histoplasma, Paracoccidioides brasiliensis, Sporothrix schenckii, Hormodendrum, Cladosporium, Blastomyces dermatitidis and various kinds of other types of yeasts and fungi. Itraconazole is not able to inhibit the growth of Rhizopus and Mucor.
One nitrogen atom contained in the itraconazole molecule can bind to the ferrous ion on the heme of the P450 molecule in the fungal cell, thereby inhibiting the P450 hydroxylase-catalyzed de-methylation of lanosterol, Sterol to ergosterol conversion blocked, lanosterol and other precursors accumulation, membrane chemical composition changes, membrane associated enzyme dysfunction, increased permeability, intracellular fluid spill, so as to achieve the inhibition and sterilization. The combination of this product with the fungus P450 system is quite strong while its combination with the mammalian P450 system is weak, so that the toxicity of drugs on human is greatly reduced. Clinical Itraconazole is mainly used for the treatment of systemic deep fungal infections caused by systems such as blastomycosis, histoplasmosis, coccidioidomycosis, chromoblastomycosis, sporotrichosis and coccidioidomycosis. It can also be used for the treatment of candidiasis and aspergillosis.
8.2 Pharmacokinetics
Itraconazole, when taken immediately after the meal, can give the highest bioavailability. After (4.6 ± 1.3) hours of oral administration of 200 mg of itraconazole, the plasma concentration can reach peak with the plasma concentration being (0.32 ± 0.16) mg/mL. The product has a plasma protein binding rate of 99.8% with the whole blood concentration being about 60% of the plasma concentration. The drug concentration in the lung, kidney, liver, bone, stomach, spleen and muscle was found to be 2 to 3 times as high as that in the corresponding plasma concentration.  In keratin-rich tissues, especially in the skin, the concentration is four times as high as that in the plasma concentration while the drug clearance is associated with the process of epidermal regeneration. If withdraw the drug after continuous medication of 4 weeks, the plasma concentration become undetectable after 7 days while drug contained in the skin can be still maintained in the drug treatment concentration for 2 to 4 weeks. After a week of starting the treatment, it can be measured of itraconazole in the keratin. At the end of the 3-month treatment course, the drug concentration can be maintained for at least 6 months. This product is present in sebum with a small amount also existing in sweat. Itraconazole is also concentrated in areas susceptible to fungal infection. The duration of the treatment concentration in the vaginal tissue is: 200mg once per day for 3 days, last for 2 days; 200mg 2 times a day for 1 day, can last 3 days. Itraconazole is mainly metabolized in the liver, producing large amounts of metabolites. One of them is hydroxylated itraconazole; in vitro study has found that it has a similar antifungal activity with this product. The level of antifungal drug measured by bioanalytical method is three times as high as the level measured by high-pressure liquid chromatography analysis. This product was biphasic in plasma clearance with the terminal half-life of (23.8 ± 4.7) hours. The dosage of the prototype drug through fecal excretion accounts for about 3 to 18% of the total dose. The prototype drug via renal excretion is less than 0.03% of the dose with about 35% being subject to urine excretion in the form of metabolites within a week.
8.3 Clinical application and indications
Itraconazole is applicable for the treatment of the following diseases:
1, it can be used for the treatment of systemic fungal infections, such as aspergillosis, candidiasis, cryptococcosis (including cryptococcal meningitis), histoplasmosis, sporotrichosis, Paracoccidioides brasiliensis disease, blastomycosis and many other kinds of rare systemic or tropical fungal diseases.
2, it can be used for the treatment of the candidiasis infection occurred in the mouth, throat (foreign data), esophageal (foreign data) and vulvovagina, and fungal conjunctivitis, fungal keratitis.
3, it can be used for the treatment of superficial fungal infections, such as hand, foot and ringworm, tinea corporis, tinea corporis, tinea versicolor and so on.
4, it can be used for the treatment of dermatophytes and (or) yeast-induced onychomycosis.
8.4 Dosage and Usage
Capsules: In order to achieve optimal absorption, itraconazole capsules should be administered immediately after a meal and the capsule must be swallowed. 1. Candida vaginitis: 200mg each time, twice a day, a course of treatment for 1 day or 200mg, once the course of treatment of 3 days; 2. Tinea versicolor: 200mg each time, once a day with the course of treatment of 7 days ; 3. Dermatomycosis: 100 mg each time, once a day with the course of treatment of 15 days; high-degree keratinized area (such as foot bottom ringworm, hand tinea) need: extended treatment of 15 days; 4 Oral candidiasis: 100mg each time, once a day with the course of treatment of 15 days; 5. Fungal keratitis: 200 mg each time, once a day with the course of treatment of 21 days; 6. For some immunodeficiency patients, such as leukemia (such as leukemia), AIDs and organ transplanted patients, application of itraconazole capsules for the treatment of fungal infections can get reduced oral bioavailability; in this case, the dose can be doubled. 7. Onychomycosis: 1) shock treatment: 200 mg each time, twice per day with continuous one week as a shock treatment. For the treatment of nail infections, it is recommended to adopt two shock treatment courses with each course having a gap of 3 weeks; for the treatment of toenail infection, it is recommended to adopt three shock treatment courses. Each treatment course has a gap of 3 weeks. 2) Or adopt continuous treatment: 200 mg each time, once a day, continue for three months. This product is removed more slowly in the skin and keratin tissue than removed in the plasma. Therefore, for skin infections, 2 to 4 weeks after stopping the drug can achieve the most ideal clinical and mycological efficacy. For the treatment of onychomycosis, people can achieve the best clinical and mycological efficacy after 6~9 months of stopping the drugs.
Injection: during the first two days, give itraconazole injection 2 times a day, later change to once per day. Treatment protocol in Day 1 and 2: 2 times per day; adopt intravenous infusion of 200 mg itraconazole 1 hour each time. From day 3: perform once per day with intravenously infusion of 200 mg of itraconazole for 1 hour each time. The safety for intravenous administration of more than 14 days is not clear.
8.5 Medicine interactions
1. Enzyme-induction Drugs: for example, rifampicin and phenytoin can significantly reduce the oral bioavailability of this product. Therefore, upon administration together with the enzyme-induction drugs, we should monitor the plasma concentration of the goods.
2 In vitro studies have showed that there was no interaction between itraconazole and imipramine, propranolol, diazepam, cimetidine, indomethacin, methotrexate and sulfadimidine regarding to the plasma protein binding.
3. It has been reported that this product, when exceeding the recommendation dosage, has interaction with cyclosporine A, astemizole and terfenadine. If these drugs are administrated together with this product, we should reduce their doses.
4. This product has been reported have interaction with warfarin and digoxin. Therefore, if these drugs are administrated together with this product, we should reduce their doses.
5. It has been not observed of the interaction of this product with AZT (zidovudine).
6. It has been not observed of the induction effects of itraconazole on the metabolism of ethinyl estradiol and norethindrone.
Adverse reactions
It is commonly observed of gastrointestinal discomfort, such as anorexia, nausea, abdominal pain and constipation. Less common side effects include headache, elevated reversible aminotransferase, menstrual disorders, dizziness and allergic reactions (such as itching, erythema, wheal and angioedema). There are a few cases that have reported Stevens-Johnson syndrome (severe erythema multiforme). The majority of patients who have had a potential pathologic change and are undergoing multiple drug regimens can get symptoms such as hypokalemia, edema, hepatitis, and alopecia during long-term treatment with itraconazole. There are individual cases that have reported the peripheral neuropathy, but whether it is related to taking itraconazole is uncertain.
Stability
This product appears as colorless to yellowish solution, should be stored at room temperature, being avoid of light and freezing. Before application, we should check whether there are particles emerging and whether there is discoloration. After the preparation of the solution, it can be stored for 48 h at room temperature or refrigerated and dark conditions.
8.6 Clinical evaluation
Tinea corporis, tinea corporis and tinea pedis can obtain the cure rate or significant efficiency of 80% or more. The cure rate of Pityriasis versicolor can be over 90%. The negative conversion ratio of vaginal candidiasis fungus can reach 80%. 80% of the cases of blastomycosis, sporotrichosis, and histoplasmosis can get clinically cured or markedly.
8.7 Precautions
1. It is recommended to check liver function in patients who have continued medication for more than 1 month and who have develop anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine during the treatment. If abnormal, they should stop medication.
2. Itraconazole is mostly subject to the liver metabolism, and thus patients of abnormal liver function should take with caution (unless the need for treatment is higher than the risk of liver damage).
3. Stop the treatment immediately upon the occurrence of neurological symptoms.
4. For patients with renal insufficiency, the excretion of the goods slows down. It is recommended to monitor the plasma concentration of this product to determine the appropriate dose.
8.8 Drug overdose
Once occurs, we should take supportive therapy, including gastric lavage. Itraconazole can’t be removed by hemodialysis with no special antidote.
8.9 Chemical properties
It is crystallized from toluene with the melting point of 166.2 °C and PKa of 3.7. It is almost insoluble in water and the dilute acid solution. Acute toxicity LD50 (14 days) mice, rats, dogs (mg/kg):> 320,> 320,> 200 orally.
8.10 Uses
The imidazole antifungal agents for the triazole ring, through inhibiting the activation of cytochrome P-450, including oxidase and peroxidase, disable the 14, α-methyl sterols to be dehydrogenated and be converted to ergosterol, so that the growth and proliferation of fungi are inhibited. They have strong lipophilicity and penetrate through the biofilm to inhibit the binding of the membrane to the fungus. The antibacterial spectrum is similar to ketoconazole. It is effective in the treatment of superficial fungal diseases such as vaginal and oral candidiasis as well as skin mycosis. Furthermore, it is expected to become the highly-efficient and safe drugs for the treatment of deep fungal infections such as cryptococcal encephalitis (AIDS). It is used for the treatment of vulvovaginal candidiasis, pityriasis and skin fungal disease pityriasis caused by sensitive fungi.
It can be used for the synthesis of broad-spectrum azole antifungal agents for the treatment of systemic infection caused by deep fungus. It can also be used for the treatment of candidiasis and aspergillosis.
8.11 Production method
Starting from m-dichlorobenzene, compound (I) can be obtained through a reaction similar to ketoconazole. The compound (I) is further condensed with 1-acetyl-4-(4-hydroxyphenyl) piperazine, followed by hydrolysis to remove the acetyl group, condensation with p-nitrochlorobenzene, hydrogenation reduction, chloroformate esterification, and reaction with hydrazine hydrate. After cyclization and alkylation, itraconazole is finally obtained. The intermediate 1-acetyl-4-(4-hydroxyphenyl) piperazine can use piperazine as the starting material and prepared with the following reactions.
8.12 Description
Itraconazole is an orally-active triazole antifungal indicated for use in the treatment of dermal, vaginal and systemic mycoses. In immunocompromised and AIDS patients, itraconazole has been shown to significantly reduce the incidence of relapses of cryptococcal meningitis.
8.13 Chemical Properties
Off-White Crystalline Solid
8.14 Originator
Janssen (Belgium)
8.15 Uses
An orally active antimycotic structurally related to Ketoconazole. Antifungal
8.16 Uses
vitamin, enzyme cofactor
8.17 Uses
Anti-infective
8.18 Uses
Anti Fungal. Used in the treatment of stomach upset/ indigestion and other gastrointestinal conditions
8.19 Uses
For the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: pulmonary and extrapulmonary blastomycosis, histoplasmosis, aspergillosis, and onychomycosis.
8.20 Uses
A traizole antifungal agent
8.21 Indications
Itraconazole (Sporanox) is effective in the treatment of histoplasmosis, blastomycosis, candidiasis, and dermatophyte infection. Its efficacy in the treatment of tinea capitis in children is equal to griseofulvin, and it is usually better tolerated (21). It is metabolized by the cytochrome P-450 system and may increase the levels ofwarfarin, cyclosporine, and digoxin among others. Its use is contraindicated with certain medications.
Itraconazole (Sporanox) is a triazole antifungal that is related to the imidazole ketoconazole. Similar to ketoconazole, it interferes with ergosterol synthesis and cell membrane integrity. It is clinically active against dimorphic fungi, yeast, dermatophytes, Blastomycetes, histoplasmosis, sporotrichosis, and Aspergillus. Itraconazole is a potent inhibitor of the cytochrome P450 3A enzyme system, which may elevate blood levels of other drugs metabolized by this system if taken concomitantly. Itraconazole levels may decrease in patients who are concurrently taking rifampin, phenobarbital, or phenytoin. Cyclosporine, felodipine, digoxin, warfarin, and oral hypoglycemic levels may increase when given in conjunction with itraconazole. Itraconazole, like ketoconazole, is contraindicated in patients taking cisapride. Itraconazole may induce torsades de pointes, ventricular arrhythmias, and congestive heart failure.
8.22 Manufacturing Process
Synthesis of cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4- dihydro-2-(methylpropyl)-3H-1,2,4-triazol-3-one is showed by the same procedure as for cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3- dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-2-propyl-3H-1,2,4-triazol-3-one described in the patent.
A mixture of 13.4 parts of 1-(4-methoxyphenyl)piperazine dihydrochloride, 7.9 parts of 1-chloro-4-nitrobenzene, 10 parts of potassium carbonate and 90 parts of N,N-dimethylformamide is stirred and refluxed overnight. The reaction mixture is diluted with water and the product is extracted twice with trichloromethane. The residue is triturated in 4-methyl-2-pentanone. The product is filtered off and crystallized from 1,4-dioxane, yielding 10.5 parts (67%) of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine; melting point 195.1°C.
A mixture of 12 parts of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine, 200 parts of methanol and 225 parts of tetrahydrofuran is hydrogenated at normal pressure and at 20°C with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and washed with N,N-dimethylacetamide. Product is filtered off and crystallized from 1-butanol, yielding 8 parts (74%) of 4-[4-(4- methoxyphenyl)-1-piperazinyl]benzenamine; melting point 191.8°C.
A mixture of 30 parts of 4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine and 300 parts of a hydrobromic acid solution 48% in water is stirred and refluxed for 10 days. The reaction mixture is evaporated and the residue is alkalized with sodium hydroxide. The mixture is filtered and the filtrate is acidified with acetic acid. The precipitated product is filtered off and crystallized from 1,4-dioxane, yielding 12 parts (44%) of 2,4-dihydro-4-{4-[4- (4-hydroxyphenyl)-1-piperazinyl]phenyl}-2-(1-methylpropyl)-3H-1,2,4-triazol- 3-one.
To a stirred solution of 2,4-dihydro-4-{4-[4-(4-hydroxyphenyl)-1-piperazinyl] phenyl}-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one in 100 parts of dimethyl sulfoxide are added 0.3 parts of sodium hydride dispersion 78% and the whole is stirred at 50°C till foaming has ceased. Then there are added 3.7 parts of cis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3- dioxolan-4-ylmethyl]methanesulfonate and stirring is continued for 3 hours at 100°C. The reaction mixture is cooled and poured onto water. The product is extracted with dichloromethane. The extracts are washed with a diluted sodium hydroxide solution and filtered. The residue is crystallized from 1- butanol. The product yield 4.3 parts (75%) of cis-4-{4-[4-{4-[2-(2,4- dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy] phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-2-(methylpropyl)-3H-1,2,4-triazol- 3-one.
8.23 Brand name
Sporanox (Janssen).
8.24 Therapeutic Function
Antifungal
8.25 Antimicrobial activity
The spectrum includes dermatophytes, dimorphic fungi (Blast. dermatitidis, Coccidioides spp., Hist. capsulatum, Paracocc. brasiliensis, Penicillium marneffei and Spor. schenckii), molds (including Aspergillus spp.), dematiaceous fungi and yeasts (Candida spp. and Cryptococcus spp.).
8.26 Acquired resistance
This is uncommon, but fluconazole-resistant C. albicans and C. glabrata are often cross-resistant to itraconazole. There are reports of itraconazole-resistant strains of A. fumigatus.
8.27 General Description
Itraconazole is an antifungal drug prescribed for oral or intravenous treatment of fungal infections. The drug is sold under trade names such as Sporanoxor Onmel?. This Certified Spiking Solution? is suitable as starting material for calibrators, controls, or linearity standards for clinical and diagnostic testing or therapeutic drug monitoring of itraconazole in patient blood, serum, or plasma samples by LC-MS/MS or HPLC.
8.28 Usage
Itraconazole is a triazole antifungal agent. It is used to inhibit cytochrome P-450-dependent enzymes and ergosterol synthesis. It has been used against histoplasmosis, blastomycosis, cryptococcal meningitis, and aspergillosis. It?s different formulations are used to study Candida strains in murine invasive infections. It has been used to study proliferative changes of the forestomach mucosa in alloxan-induced diabetic rats..
9. Computational chemical data
  • Molecular Weight: 705.641g/mol
  • Molecular Formula: C35H38Cl2N8O4
  • Compound Is Canonicalized: True
  • XLogP3-AA: null
  • Exact Mass: 704.2393071
  • Monoisotopic Mass: 704.2393071
  • Complexity: 1120
  • Rotatable Bond Count: 11
  • Hydrogen Bond Donor Count: 0
  • Hydrogen Bond Acceptor Count: 9
  • Topological Polar Surface Area: 101
  • Heavy Atom Count: 49
  • Defined Atom Stereocenter Count: 0
  • Undefined Atom Stereocenter Count: 3
  • Defined Bond Stereocenter Count: 0
  • Undefined Bond Stereocenter Count: 0
  • Isotope Atom Count: 0
  • Covalently-Bonded Unit Count: 1
  • CACTVS Substructure Key Fingerprint: AAADcfB/+AAGAAAAAAAAAAAAAAAAAWJEAAA8YMEAAAAAAAAB1AAAHgIIAAAADD7hmCY33ocIFACqAiRDdACSCAsxp4AfyAAOboifbiLFu5u3OCjtxhPe6CewwKAOBECAAACBAAAIgQAAAQIAAAAAAAAAAA==
11. Realated Product Infomation