CN1244125A

CN1244125A - Use of cis-hydroxyitraconazole in order to advoid side-effects of itraconazole and hydroxyintraconazole

Info

Publication number: CN1244125A
Application number: CN 97181244
Authority: CN
Inventors: J·R·麦库洛; P·科克
Original assignee: Sepracor Inc
Current assignee: Sunovion Pharmaceuticals Inc
Priority date: 1996-11-12
Filing date: 1997-11-11
Publication date: 2000-02-09
Also published as: WO1998020876A1; AU715999B2; CA2271849A1; AU5172098A; JP2001504119A; EP0942725A1

Abstract

The present invention provides prophylactic methods and treatment methods using cis-hydroxyitraconazole, a metabolic derivative of cis-itraconazole, for the treatment or prevention of microbial, particularly fungal infection and other disorders, while avoiding the concomitant liability of adverse side effects associated with the administration of cis-itraconazole. Methods of treating or preventing such infections in the brain and other areas of CNS are also disclosed.

Description

Use cis-hydroxyl Itraconazole to avoid the side effect of Itraconazole and hydroxyl Itraconazole

1. technical field

The present invention relates to adopt the metabolic derivative of cis-hydroxyl Itraconazole, cis-Itraconazole and derivant thereof to be used for the treatment of antibacterial, microorganism and fungal infection and other disease, avoid the Therapeutic Method of the incident adverse side effect relevant simultaneously with taking Itraconazole.The hydroxyl Itraconazole has chemical formula 4-, and (((4-((2 for 4-for 4-, the 4-Dichlorobenzene base)-2-(1H-1,2,4-triazol-1-yl methyl)-1,3-dioxolanes-4-yl) phenyl methoxyl group))-and the 1-piperazinyl) phenyl)-2,4-dihydro-2-(2-hydroxyl-1-methyl-propyl)-3H-1,2,4-triazole-3-ketone.(the CAS registration number is 112559-91-8).The invention still further relates to the Therapeutic Method and the pharmaceutical composition of the chemical compound that adopts following structure:

Wherein R be hydrogen ,-P (O) (OH) ₂Or-SO ₃H.

2. background 2.1 Itraconazoles of the present invention and hydroxyl Itraconazole

Itraconazole-a kind of has formula C ₃₅H ₃₈Cl ₂N ₈O ₄Chemical compound be commercial with SPORANOX ^The synthesis of antifungal agents of selling.Itraconazole is four diastereomers (two enantiomer to), each has 1: 1: 1 of three chiral centres: 1 racemic mixture.Itraconazole is a kind ofly to have Orally active, broad-spectrum antifungal agents, and structurally relevant with miconazole and clotrimazole.

After oral, Itraconazole is slowly absorbed.Take every day, and blood plasma level reaches peak value after 15 days, and the pharmacokinetics behavior of Itraconazole is non-linear.Described chemical compound is several inactive metabolite by the metabolism of bioactive hydroxyl Itraconazole finally.Metabolism obviously is to be undertaken by the mechanism of liver, and does not in most of the cases have metabolite through homaluria.Referring to people such as Hardin, Antimicro.Agents and Chemotherapy, 32:1310-1313 (1988).

Itraconazole extensively is distributed in the lipophilic tissue, makes 2-20 that concentration reaches corresponding plasma concentration doubly.Show that in external various researchs Itraconazole has suppressed synthetic based on Cytochrome P450 of ergosterol, and this is a key component of fungal cell membrane.This causes the increase of permeability and the seepage of cellular content usually.Under high concentration, the inner cell organ of cell is degenerated, and peroxisome increases, the variation that may necrose.Show the activity that suppresses Blastomyces dermatitidis, capsule tissue spore slurry bacterium, the spore slurry bacterium Du Shi of capsule tissue mutation, Aspergillus flavus, Aspergillus fumigatus and novel Cryptococcus at external Itraconazole, and active to the sporadic inhibition of other fungus kind.

The taboo Itraconazole is taken with cisapride, RMI 9918 or astemizole.Other possible various taboos of taking Itraconazole comprise: idiosyncrasy hepatitis, Cardiac Dysthythmia and in some cases death.Because when taking with Itraconazole, oral midazolam or triazolam also can cause the increase of plasma concentration, so these medicines should not use with Itraconazole.

Itraconazole also is effective inhibitor of a kind of CYP3A4, and CYP3A4 is relevant with the metabolism that many kinds of medicines comprise lovastatin.The someone reports that Itraconazole has significantly increased the plasma concentration of this pravastatin and caused toxicity recently, i.e. skeletal muscle toxicity or myopathy.Referring to Neuvonen and Jalava, Clin.Pharmacol.Ther., 60 (1): 54-61 (1996).

Itraconazole becomes various metabolite by liver metabolism in human body.Specifically, Itraconazole is generated 3-hydroxyl-2-butyl group by CYP3A4 institute hydroxylating on the sec-butyl side chain, obtain active metabolite hydroxyl Itraconazole.(for example referring to people such as Mikami, " In VitroAntifungal Activities of Hydroxy-Itraconazole, An ActiveMetabolite of Itraconazole ", Chemotherapy, 42:290-296 (1994)).United States Patent (USP) the 4th, 791, the plethora that discloses all cpds (comprising the hydroxyl Itraconazole) No. 111, and describe these chemical compounds and in homoiothermic animal, can be used for suppressing fungus and antibacterial.Itraconazole has 3 spatial chemistry (stereogenic) center, and the hydroxyl Itraconazole has 4 spatial chemistry centers, and 16 stereomeric forms are provided: 8 cis-isomers and 8 trans-isomers.

For suppressing some fungus kind, the antifungal activity of hydroxyl Itraconazole has shown and can compare with Itraconazole.(referring to Physician ' s Desk Reference ^, 1305-1307 page or leaf, the 50th edition, Medical Economics Data Production Co., N.J., 1996).It is more effective that the somebody reports that Itraconazole suppresses fungal infection than hydroxyl Itraconazole usually.(for example referring to people such as Mikami, " In Vitro Antifungal Activitiesof Hydroxy-Itraconazole, An Active Metabolite ofItraconazole ", Chemotherapy, 42:290-296 (1994)).Yet for pyrroles's antifungal, between the inhibition concentration of external minimum and clinical data, do not set up correlation as yet.Hydroxyl Itraconazole and Itraconazole both are the inhibitor of Cytochrome P450 3A4 enzyme system.Therefore, in them each with mainly by Cytochrome P450 3A4 enzyme system metabolic medicine all will cause when taking can increase or the increase of extended treatment and adverse effect such as ARR plasma concentration.(referring to Neuvonen and Jalava, " Itraconazole Drastically Increases Plasma Concentrations ofLovastatin and Lovastatin Acid ", Clin.Pharmaco.Ther., 60 (1): 54-61 (in July, 1996) (Lovastatin); People such as Honig, J.Clin.Pharmacol., 33:1201-1206 (1993) (interacting) with RMI 9918.

In the treatment human body, use Itraconazole to show some disadvantageous side effect in the fungal infection, comprise (but being not limited thereto): unusual liver function and toxicity, Cardiac Dysthythmia, libido reduction, dizziness, edema, fatigue, fever, gastrointestinal disorder, as nausea,vomiting,diarrhea, stomachache and anorexia, headache, hypertension, hypokalemia, sexual impotence, discomfort, pruritus, erythra and drowsiness.

In preventing a progress of the various shortcomings of Itraconazole, United States Patent (USP) the 5th, 474, disclose for No. 997 adopt optically pure (2R, 4S)-method and composition of Itraconazole.Described method relates to fungus, yeast and the dermatophytosis for the treatment of locality and general and infects, and has avoided the incident various detrimental effects relevant with the raceme Itraconazole simultaneously.

We also know some drugs, can disturb Cytochrome P450 as ketoconazole and/or erythromycin, take this to suppress the metabolism of infection or antiphlogistic chemical compound such as Itraconazole.Owing to disturb the Itraconazole metabolism, therefore also exist potential unfavorable interaction between the infection of more Itraconazole or other known inhibition Cytochrome P450 or the antiphlogistic medicine.

We know that Itraconazole has some disadvantageous effect, comprises those side effect that (but being not limited thereto) is above-mentioned.This disadvantageous oxidative metabolism that cis-Itraconazole disturbed or suppressed several drugs that act as.The biochemical basis of this inhibition comprises the drug interaction of cis-Itraconazole and Cytochrome P450.This Cytochrome P450 system relates to various medicines, comprises the metabolism of (but being not limited thereto) three ring-type antidepressants, non-sedative antihistamine agent, anti-arrhythmic and beta-adrenergic blocking agent.Referring to Stevens and Wrighton, J.Pharm.Exp.Therap.266 (2): 964-971 (1993).Itraconazole suppresses drug metabolism its clinical use is existed an important limitation, because of it has the metabolism of the medicine that change takes subsequently or take together and the potential ability of pharmacokinetics.The interaction of this medicine has as a result limited the safe handling of Itraconazole and some other medicines (when taking subsequently or taking with Itraconazole simultaneously).(referring to Physician ' s DeskReference ^, 1305-1307 page or leaf, the 50th edition, Medical Economics DataProduction Co., N.J., 1996).2.2 secondary infection and mycosis

The fungal disease of general (whole body mycosis) is normally chronic, for being brought out by the chance pathogenic fungi by pathogen under the improper situation, and the disease of very slow development.Yet they may become pathogen when it enters the host who is encroached on by HIV, ionizing radiation, corticosteroid, cancer, immunosuppressant etc. or under the disease of emphysema, bronchiectasis, diabetes, leukemia, burn etc.The symptom of this fungal disease is normally not intensive, may comprise fever, feels cold, anorexia and weight loss, not accommodate depression.Fungal disease is limited in the distribution on the typical anatomy usually, and many primary lesioies that relate in the lung are when fungus has how concrete fungal infection feature performance when primary lesion is propagated.For example, coccidioidomycosis takes place as former form of the respiratory disorder acute, optimum, that the course of disease is limited, and disease develops into from former state gradually that chronic, normally fatal skin infection, lymph node infect, spleen infects and liver infects.Similarly, blastomycosis is mainly concerned with lung, and extends to skin occasionally.Other infectious disease such as paracoccidioidomycosis have different processes with candidiasis, depend on whether the cause of disease shows several forms that relate to skin, mucosa, lymph node and internal.The diagnosis of concrete fungal disease is by separating pathogenic fungus from expectorant, urine, blood or bone marrow, or by carrying out according to the popular fungus form of tissue intrusion.

The fungal infection on surface is owing to the dermatophytosis or the fungus that relate to skin outer layer, hair or fingernail are caused.Infection may cause gentle inflammation, and cause alleviation intermittently and propagate gradually, enlarge increase the weight of, increase damage.The yeast infection that comprises candidiasis, oral area candidiasis (thrush) is confined to skin and mucosa usually, and symptom is different with the difference that infects the position.Generally speaking, infect and to be erythema, can itch usually, between axillary fossa, umbilical part, groin, toe and refer to be on the web exudative speckle.The oral area thrush relates to the tongue or the buccal mucosa of inflammation, and the exudate speckle that is white in color, and being characterized as on forehead or nose of chronic mucocutaneous candidiasis takes on a red color, it is the pus born of the same parents, that crust to rise, damage thickening.

Many " health azoles (conazole) " antifungal (comprising Itraconazole) has same disadvantageous effect.These disadvantageous effects comprise that (but being not limited thereto) feels sick, vomiting, anemia, thrombocytosis, hypersensitivity reaction, hepatocyte toxic and some central nervous system's toxicity.The racemic mixture that it has been found that Itraconazole causes nausea and vomiting, anorexia, headache and dizziness.The reaction of hepatocyte toxic and hypersensitivity comprises urticaria, and the raising of serum liver enzyme is also with to take described medicine relevant.The hepatocyte toxic is a kind of not too general but even more serious detrimental effect.In fact, because there is the serious consequence of the low influence of potential hepatocyte toxic, we do not approve of to use the oral medicine azoles as first-line antifungal usually.(for example referring to people such as Lavrijsen, Lancet 340:251-252 (1992)).2.3 the secondary infection of CNS

Usually in the patient of the patient of non-responsiveness, particularly infected by HIV, other position of brain or central nervous system (" CNS ") is fixed in secondary infection.The infection of these types is difficult to treat, because activating agent can't and be penetrated into CNS by blood brain barrier.In addition, various medicines that can effective or invalid infiltration blood brain barrier can cause CNS to poison usually.Therefore need a kind ofly have significantly antibiotic or antifungal is active and have by blood brain barrier and do not cause remarkable toxic activating agent obviously.

Though there has been the people to do some prophesies with regard to molecule by the ability of blood brain barrier, these prophesies only are to infer at the most.General people consider that a kind of chemical compound enters the speed and the degree of brain, is mainly determined by its partition coefficient, ionization constant and molecular size.Single distribution dicyandiamide solution do not occur as general applicable pattern (though the capryl alcohol aqueous systems is paid close attention to especially) for brain infiltration, and Hansch and colleague thereof propose, for entering CNS, to be about 100 be optimum to partition coefficient in this system.(referring to Glave and Hansch, J.Pharm.Sci., 61:589 (1972); People such as Hansch, J.Pharm.Sci., 76:663 (1987)).But the structure of optimizing a kind of chemical compound is to improve the reduction that the brain infiltration may cause its effect.Therefore, basic difficulty is to optimize the permeability and the compound functions of blood brain barrier.

The exploitation a kind of medicine, particularly a kind of be generally used for the bonded therapeutic scheme of other therapies in antifungal the time must consider many factors.For example, the interaction of the various physical properties of compounding pharmaceutical, bioavailability, effect, medicine, drug metabolism, toxicity etc.The relative polarity of Itraconazole and indissolubility are difficult in the non-intestinal solution it and are prepared.In addition, owing to the interaction (hepatic metabolism) between Itraconazole and the cytochrome P-450 and because these medicines are typically found at CNS, particularly brain to its effective fungus and bacterial infection usually, make that the use of these medicines is limited to.Similarly, because Itraconazole is usually with antiviral agents, antibiotics, antihistaminic, antidepressants, antiarrhythmics, antineoplastic agent, beta-receptor blocade and hypocholesterolemia agent or its various combinations whiles or unite and give patient, so the interaction between the medicine is a main Consideration.

Need especially various compositionss of exploitation and method to be used for the treatment of above-mentioned antibacterial, fungus or other infected by microbes, and reduce simultaneously drug metabolism inhibition, reduce disadvantageous drug interaction, reduce the hepatocyte toxic and improve selectivity, CNS permeability and total effect.

3. summary of the present invention

We find that now cis-hydroxyl Itraconazole is the medicine of a kind of effective treatment body local and systemic infection, and significantly reduce simultaneously or avoid various disadvantageous side effect, comprise (but being not limited thereto) hepatocyte toxic, suppress drug metabolism, drug interaction and with Qt during prolong relevant cardiac side effects.In addition, we find that also cis-hydroxyl Itraconazole is the medicine that a kind of effective treatment is positioned at the secondary opportunistic pathogenesis infection at brain or other position of CNS.Cis-hydroxyl Itraconazole can permeate blood brain barrier and optionally interact to effect a radical cure described fungal disease by minimum hepatocyte toxic and the toxic cost of CNS with fungal cell's cytochrome p 450.The use of cis-hydroxyl Itraconazole provides a kind of effective treatment locality and general fungus, yeast and other dermatophytosis to infect, and reduces the method for detrimental effect simultaneously.

The inventive method provides various infection and inflammation in a kind of treatment human body, and avoids usually the method for the adverse side effect relevant with taking all cpds such as Itraconazole simultaneously.These disadvantageous side effect comprise prolongation during (but being not limited thereto) unusual liver function, Cardiac Dysthythmia, libido attenuating, dizziness, edema, fatigue, fever, gastrointestinal disorder such as nausea,vomiting,diarrhea, stomachache and anorexia, headache, hypertension, hypokalemia, sexual impotence, discomfort, the QT, pruritus, erythra and drowsiness.

The present invention also comprises by cis-hydroxyl Itraconazole, phosphate derivative, sulfate-derivatives or its pharmaceutically acceptable salt of taking the treatment effective dose for described patient and treats the infected by microbes of locality or general, and avoids the method for incident various adverse side effects relevant with taking Itraconazole simultaneously.

The present invention comprises that also infected by microbes, bacterial infection, fungal infection, yeast infection, the dermatophytosis of treatment locality or general infect or the whole bag of tricks of inflammation, by cis-hydroxyl Itraconazole or its pharmaceutically acceptable salt of taking the treatment effective dose for described patient, each method can both reach its separately purpose and avoid the incident various adverse side effects relevant simultaneously with taking cis-Itraconazole.

Method of the present invention can achieve the goal and avoid suppressing the metabolism of other medicines by the Cytochrome P450 approach simultaneously basically.The treatment effective dose of cis-hydroxyl Itraconazole is generally about 1.0 milligrams-Yue 1000 mg/day, more preferably about 10 milligrams-Yue 500 mg/day.The cis of described amount-hydroxyl Itraconazole, phosphate derivative, sulfate-derivatives or its pharmaceutically acceptable salt can be taken with pharmaceutically acceptable carrier.

Method of the present invention comprises the treatment bacterial infection, comprises (but being not limited thereto) erysipelothrix rhusiopathiae (Erysipelotric insidiosa), staphylococcus such as staphylococcus haemolyticus, or Streptococcus, as streptococcus pyogenes; And fungus, yeast and dermatophytosis infect, and comprise (but being not limited thereto) aspergillosis, Aspergillus fumigatus, blastomycosis, Blastomyces dermatitidis, sick and the oral candidiasis (thrush) of candida albicans, Candida albicans, Oidium tropicale, coccidioidomycosis, cryptococcosis, Cryptococcus histolyticus, Ctenomyces mentagrophytes, histoplasmosis, Sabouraudites lanosus, Mucor is various, tinea unguium, blastomyces brasiliensis, Phialophora verrucosa, pityrosporum ovale, Saprolegnia is various, Shen gram side spore, Sporothrix schenckii, Trichophyton mentagrophytes and trichophyton purpureatum.

The invention still further relates to the pharmaceutical composition that is used for the treatment of human body, it comprises cis-hydroxyl Itraconazole or its pharmaceutically acceptable salt of pharmaceutically acceptable carrier and treatment effective dose.

Cis-the amount of hydroxyl Itraconazole in compositions is generally about 50 milligrams-Yue 1200 milligrams, but its amount is about 100 milligrams-Yue 1000 milligrams in preferred embodiments.Described compositions can oral, non-gastrointestinal (intravenous) or topical.Above-mentioned composition can be chosen wantonly and contain one or more other active component, comprises antifungal.

The present invention comprises that also employing has interactional treatment general and the antibacterial of locality or the improving one's methods of fungal infection that strengthens effectiveness, improvement dissolubility, enhanced bioavailability, the ability that possesses infiltration CNS, selectivity inhibition fungal cell's cytochrome p 450 and reduce cardiac side effects or disadvantageous medicine.These chemical compounds have following formula: Wherein R be selected from hydrogen ,-P (O) (OH) ₂,-SO ₃H or its salt.Four asymmetric carbon (representing with asterisk) are arranged in the chemical constitution of these chemical compounds: two on the sec-butyl side chain of triazolone, two on dioxolanes.These chemical compounds are specially adapted to treat the patient's of the patient of non-responsiveness, particularly infected by HIV the fungal infection of brain.

The present invention also comprises the method by the candidiasis infection of the following formula: compound treatment human central nervous system of taking the treatment effective dose to the people:

Wherein R be hydrogen ,-P (O) (OH) ₂,-SO ₃H or its pharmaceutically acceptable salt.In one embodiment, find that infection site to be treated is positioned at brain.In a preferred embodiment, avoided cis-hydroxyl Itraconazole and suppress interaction between the medicine of Cytochrome P450.The amount of the cis of taking-hydroxyl Itraconazole is generally about 1 milligram-Yue 1000 mg/day.4. the present invention describes in detail

Present invention resides in and treat or prevent to be selected from the infection that antibacterial, fungus, yeast or dermatophytosis infect in the human body, and avoid the method for incident various adverse side effects relevant simultaneously with taking Itraconazole, it comprises cis-hydroxyl Itraconazole or its pharmaceutically acceptable salt of taking the treatment effective dose to described patient.

The present invention comprises that also treatment or prevention central nervous system comprise that antibacterial, fungus, yeast or the dermatophytosis of (but being not limited thereto) brain infect, and it comprises that the patient to this treatment of needs takes the cis of effective dose-hydroxyl Itraconazole or its pharmaceutically acceptable salt.Specifically, the present invention includes the chemical compound that uses following formula: Wherein R is-PO (OH) ₂,-SO ₃H or its salt.Thereby the derivant of these cis-hydroxyl Itraconazole is because its infiltration CNS or by the ability that blood brain barrier and the interaction that suppresses fungus CP450 by selectivity suppress fungal infection more than the interaction that the suppresses human body CP450 advantageous particularly that seems.

The present invention also comprises the pharmaceutical composition that is used for the treatment of or prevents above-mentioned normal or non-responsiveness or immunosuppressant patient's infection; it comprises the cis-hydroxyl Itraconazole of pharmaceutically acceptable carrier and treatment effective dose, or phosphate derivative, sulfate-derivatives or its pharmaceutically acceptable salt.

As mentioned above, the hydroxyl Itraconazole contains four (4) individual asymmetric carbon, and it is trans to obtain ten six (16) individual stereoisomer-eight cis and eight.The present invention only comprises cis-hydroxyl Itraconazole, and comprises raceme cis-hydroxyl Itraconazole, and the optically pure isomer of eight (8) individual cis-hydroxyl Itraconazoles and its any can separation or the combination of preparation in addition.For the Therapeutic Method of institute's claim, the present invention should be interpreted as by those skilled in the art and comprise that specifically use contains the method for compositions of these isomers or its mixture.

We find, compare with Itraconazole, when cis-hydroxyl Itraconazole or its pharmaceutically acceptable salt or stereoisomer take for the patient who needs infection or anti-inflammatory treatment, it is advantageously: avoided prolonging relevant incident cardiac side effects with the QT interval, given enhanced effectiveness, increased bioavailability, improved conveying capacity by blood brain barrier, reduced the interaction of the medicine-enzyme of Cytochrome P450 base, reduced the hepatocyte toxic, and made with the interaction ratio of fungal cell's cytochrome p 450 stronger with the interaction of human body cell cytochrome p 450.

We believe, take and use other therapies when cis-hydroxyl Itraconazole in this Therapeutic Method makes the treatment doctor can adopt cis-hydroxyl Itraconazole therapy more easily at the same time or in succession.Make so a successive treatment plan of better complete sum can be arranged.Adopt cis-Itraconazole to be difficult for accomplishing this point, because the doctor must consider the half-life and the tissue distribution of disadvantageous drug interaction, weak point, and this can be derived from the inhibition effect of Itraconazole, the medicine of taking together, or both.The present invention not only makes the treatment doctor get involved in taking of another medicine in succession quickly after cis-hydroxyl Itraconazole treatment, and other medicines can with combination of cis-hydroxyl Itraconazole or parallel use because we believe that the latter can not disturb the former metabolism.Cis that Here it is-hydroxyl Itraconazole obviously is better than cis-Itraconazole part.

Cis-hydroxyl Itraconazole is not same inhibition Cytochrome P450 system on therapeutic dose, thereby can safer and more promptly be used in succession or collaborative therapy simultaneously.Therefore other medicines can be used in combination after cis-hydroxyl Itraconazole or with cis-hydroxyl Itraconazole as antidepressants, anti-arrhythmic, hydryllin, antibiotics, antifungal and other medicines described herein.

Thereby, we find when cis-hydroxyl Itraconazole and inhibition or by the metabolic medicine of Cytochrome P450, comprise when (but being not limited thereto) ketoconazole, cisapride, lovastatin, RMI 9918, fluoxetine, astemizole, loratadine, midazolam, triazolam and other medicines known in those skilled in the art are taken simultaneously, compare with described medicine simultaneously with cis-Itraconazole, it obtains minimizing with interaction between the described medicine.

Therefore, the present invention also comprises a kind of interaction of avoiding between medicine and the Cytochrome P450 system, and can treat simultaneously in the human body because the method for the caused infection of microorganism (as antibacterial, fungus, dermatophytosis), wherein said patient takes cis-hydroxyl Itraconazole or phosphate derivative, sulfate-derivatives or its pharmaceutically acceptable salt.

Term " detrimental effect " or " adverse side effect " comprise (but being not limited thereto) unusual liver function, hepatocyte toxic, Cardiac Dysthythmia, prolong relevant various cardiac side effects with the QT interval, as heart arrhythmia, disadvantageous drug interaction, libido reduction, dizziness, edema, fatigue, fever, the intestines and stomach disease, headache, hypertension, hypokalemia, sexual impotence, discomfort, pruritus, erythra and drowsiness, or its various syndromes.Term " the intestines and stomach disease " comprises (but being not limited thereto) nausea,vomiting,diarrhea, stomachache and anorexia, and various syndrome.Someone reports and takes the danger that some health azoles may increase cardiac arrhythmias.Have and report that arrhythmia is a kind of side effect of the raceme Itraconazole of general, it is reported, a kind of arrhythmia one torsades de pointes (Torsades de Pointes) of special hypotype can take place when racemic Itraconazole and RMI 9918 are taken simultaneously.Lack the unusual clinical report of many arrhythmias or QT and only reflected less relatively patient crowd at present.

Phrase " treatment effective dose " refers to can provide the amount of the cis-hydroxyl Itraconazole for the treatment of benefit in treatment or control infection and other disease.

Term " anti-infective " comprises (but being not limited thereto) antibacterium, antimicrobial, antifungal, anti-various yeast and anti-dermatophytosis or its various combinations.Term " infection " comprises that bacterial infection, infected by microbes, fungal infection, yeast infection and dermatophytosis infect, or its various combinations.

The big young pathbreaker of cis-hydroxyl Itraconazole prevention or therapeutic dose in the control of acute with chronic disease with the sanatory order of severity and route of administration different and different.Described dosage and administration frequency also will be according to age, body weight and the reactions of individual patients and are different.Generally speaking, for various diseases described herein, total daily dose be about 0.1 milligram to being less than about 10 milligrams, with the oral dose of single dose or gradation, part, percutaneous or by the inhalation topical.For example, preferred oral daily dose scope should be about 0.1 milligram to about 5 milligrams, more preferably about 0.2 milligram to about 1 milligram.

We also recommend child, age to surpass when 65 years old patient and those renal functioies or the damaged patient of liver function begin and accept low dosage, and then increase (titrate) gradually according to its discrete reaction or blood levels.Need to use these scopes dosage in addition in some cases, this it will be apparent to those skilled in the art that.It shall yet further be noted that the reaction according to individual patients in addition, how and when clinicist or treatment doctor should understand interrupts, adjustment or stopped treatment.

Term " the treatment effective dose of cis-hydroxyl Itraconazole or pharmaceutically acceptable salt or its stereoisomer " and " the treatment effective dose of cis-hydroxyl Itraconazole or its pharmaceutically acceptable salt " are included in the above-mentioned administration frequency and dosage.

Can adopt any suitable route of administration that the cis-hydroxyl Itraconazole of effective dose the method according to this invention is provided for patient.For example, can adopt the form of various administrations such as oral, rectum, non-gastrointestinal, intravenous, part, percutaneous, subcutaneous, intramuscular.The form of medicament comprises tablet, lozenge, dispersion liquid, suspension, solution, capsule, patch etc.

The pharmaceutical composition that is used for the inventive method comprises the cis-hydroxyl Itraconazole as active component, metabolic derivative or its pharmaceutically acceptable salt of cis-Itraconazole, and can contain pharmaceutically acceptable carrier, and other optional therapeutic component.

Term " pharmaceutically acceptable salt " refers to the salt of preparation from pharmaceutically acceptable, avirulent acid or alkali (comprising inorganic or organic acid).The example of these mineral acids is hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid and phosphoric acid.Suitable organic acid can be selected from, the organic acid of for example aliphatic class, aromatic species, carboxylic acids and sulfonic acid class, its example are formic acid, acetic acid, propanoic acid, succinic acid, hydroxyacetic acid, glucuronic acid, maleic acid, furancarboxylic acid, glutamic acid, benzoic acid, ortho-aminobenzoic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic (Piao's acid), methanesulfonic acid, ethyl sulfonic acid, pantothenic acid, benzenesulfonic acid, stearic acid, sulfanilic acid, algenic and galacturonic acid.The example of this inorganic base (can form salt with sulfate of the present invention or phosphate compounds) comprises the slaine that makes from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.The suitable optional N freely of organic base, N-dibenzyl-ethylenediamin, chloro procaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucosamine), lysine and procaine.

The compositions that is used for the inventive method comprises various compositionss, as suspension, solution and elixir, aerosol, or various carriers, as starch, sugar, microcrystalline Cellulose, diluent, granulating agent, lubricant, binding agent, disintegrating agent etc., (as powder, capsule and tablet) is preferable over oral liquid with oral solid formulation in the situation of oral solid formulation.Most preferred oral solid formulation is a tablet.

Because of tablet and capsule are easy to take,, in these situations, use the solid medicinal carrier so it is representing the form of best oral dosage units.As needs, can pass through the technology of standard water solution or non-aqueous solution with tablet coating.

Except above-mentioned general dosage form, the chemical compound that is used for the inventive method also can be by mode and/or the conveyer device such as the United States Patent (USP) 3,845,770,3 of sustained release, 916,899,3,536,809,3,598,123 and 4,008, (these disclosed contents are incorporated this paper herein by reference into) described in 719 carries out administration.

Be used for the inventive method and be suitable for the form that pharmaceutical composition for oral administration can be individual, as capsule, cachet or tablet, or the form of aerosol spray, what each contained scheduled volume is powder or granule, or the active component of the solution in liquid, aqueous or the on-aqueous liquid or suspension, oil-in-water emulsion or water-in-oil emulsion.These compositionss can be prepared by any pharmaceutical methods, but all methods all comprise the step that active component and the carrier of forming one or more required compositions are mixed together.Generally speaking, the solid carrier by making active component and liquid-carrier or segmentation or both carry out all evenly mixing closely, then as product need be made required form prepare as described in compositions.

For example, by compacting or molded, optional one or more auxiliary agents that adopt can prepare tablet.The tablet of compacting can pass through compression free-flowing form such as powder or particulate active component on suitable machine, chooses wantonly with binding agent, lubricant, inert diluent, surfactant or dispersant to prepare.Molded tablet can make by the molded mixture that carries out moistening powdered compounds with inert liquid diluent on suitable machine.Best each tablet contains has an appointment 0.1 milligram to being no more than about 10 milligrams active component, and each cachet or capsule contain has an appointment 0.1 milligram to being no more than about 10 milligrams active component, i.e. cis-hydroxyl Itraconazole.

Can adopt microbiology and pharmaceutical research with the broad spectrum of activity of determining to have anti-many funguses, yeast and dermatophytosis, distribute as the optically pure enantiomer of hydroxyl Itraconazole of antifungal and the relative effectivenes and the characteristic of racemic mixture.

About the antimicrobial acivity of above-mentioned all cpds, selected experiment is used for the useful antimicrobial acivity of declarative description, and under any circumstance the present invention is not construed as limiting, and comprises the category of chromatophile microorganism.Resist various funguses and antibacterial performance at the external antifungal health azoles of estimating down in several concentration (mcg/ml).(referring to Van Cutsem, people such as Chemotherapy38 Suppl.1:3-11 (1992) and Van Cutsem, Rev.Infect.Dis.9 Suppl.1:S15-S32 (1987)).Carry out in the SabouraudShi liquid (1 gram neopeptoneDifco and 2 gram glucose Difco in per 100 ml distilled waters) of the test of inhibition fungus in 16 * 160 millimeters test tubes, each contains 4.5 milliliters at 5 minutes liquid medium of 120 ℃ of following autoclave sterilizations.In 50% ethanol, initial concentration is 20 mg/ml with the compound dissolution tested.Solution is 10 mg/ml with aseptic distilled water diluting to concentration subsequently.In distilled water, carry out successive decimal scale dilution.0.5 ml soln of described medicine is joined in the test tube that contains 4.5 milliliters of SabouraudShi liquid mediums, take this to obtain the concentration of 1000,500,100,10 and 1 mcg/ml medium.By 0.5 ml distilled water is added in 4.5 mL media, adds ethanol obtaining and to contain the identical concentration of 1000 and 500 microgram medicines, thereby make the contrast test tube.Thread fungus is hatched 2-3 week in 25 ℃ SabouraudShi agar.Then 2 * 2 * 2 millimeters block is inoculated in the medium.All cultures all carry out repeated trials, and hatch 14 days at 25 ℃.The antifungal activity of hydroxyl Itraconazole is enhanced in the Sabouraud culture fluid of the external Ox blood serum that contains 10% passivation, and depends on used test(ing) medium.Hatch after 14 days and can observe the growth that has suppressed following strain in the Sabouraud culture fluid fully or significantly: the little spore of Canis familiaris L. is mould, Trichophyton mentagrophytes, candida albicans, sporothrix schenckii, blastomyces brasiliensis, Blastomyces dermatitidis, Histoplasma spp., aspergillus spp. and other fungus and antibacterial.Concentration/the response curve that can compare hydroxyl Itraconazole, its derivant and standard drug such as miconazole relevant range and effect.

Hydroxyl Itraconazole activity in vivo can with the experiment Cavia porcellus in dermatocandidiasis (candidosis) and the vaginal candidiasis of rat compare.By adopting Candida albicans to bring out vaginal infection and assess the activity in vivo of described chemical compound in vaginal candidiasis the Wistar of oophorectomize and hysterectomy rat (100 gram) (carrying out subcutaneous treatment with the estradiol undecylate in the 100 microgram Oleum sesami weekly).False estrous animal carries out intravaginal with the Candida albicans in the fixed concentration normal saline and infects.Fixed natural law is estimated the contrast of infecting or curing by obtaining vaginal smear after infection.Can be given in the to be assessed and medicine relatively that prevents or treat on the basis of mg/kg, judge its effectiveness by the ratio of negative animal in sum in each medicine group of comparison.In similar research, suppress the oidiomycotic activity of guinea pig skin people such as (, Chemotherapy, 17:392 (1972)) Van Cutsem and provide the foundation for the test The compounds of this invention.

Impel ARR current potential by check that the hydroxyl Itraconazole is assessed heart action potential and inotropic influence in human body, rabbit and dog heart.

Torsades de pointes is a kind of known antiarrhythmic medicine, and as the side effect of chinidine, sotalol and acetyl group procainamide, it causes the polar again prolongation of heart.All these medicines have the ability that blocking-up is called as potassium channel in the cell that postpones appliance (IK) jointly, and mechanically to bring out the syndromic ability of torsades de pointes relevant with it to suppose this usually.(referring to people such as Zehender, Cardiovascular Drugs Ther.515-530 (1991)).

The increase of QT persistent period and action potential duration can be used to explanation and causes ARR effect in Cavia porcellus of exsomatizing or rabbit hearts.Heart pours into the TyrodeShi solution of the oxygenation that contains 0.0,1.0,5.0,10.0 or 30.0 micromole's raceme Itraconazoles.From heart electrode, measure QT persistent period and action potential duration (APD).In independent experiment, heart is divided into 3 subgroups of accepting Itraconazole or hydroxyl Itraconazole to determine that it is separately to the influence of QT persistent period and APD.

In order to observe intravital influence the device that is used to measure blood pressure and EKG is installed with the mongrel anesthesia of two kinds of sexes of heavy 5-20 kilogram and by standard technique.The solid state sensor of dP/dT is positioned in the left ventricle, and puts into epicardial lead.Test compound injects with the dosage that increases gradually, since 2 microgram/kilograms/minute reach 15 minutes, and increases gradually till the generation cardiovascular withers.Measured parameter has: blood pressure, heart rate, dP/dT and QT interval.Chemical compound according to test is measured hematodinamics and electroactive.

External, in microsome, human lymphocyte and the cell culture system of people liver, estimate the probability of impelling the hepatocyte toxic.Hepatomicrosome makes from people's liver.Tissue is thawed, carry out homogenize among the KCl of the 0.15M in the Polytron homogenizer then.Homogenate is centrifugal, make precipitate suspend again and homogenize in the KCl of 0.15M.To sample aliquot freezing and storage under-70 ℃.Human lymphocyte is sterilely separated from the human blood of fresh, heparinization.Blood dilutes with the minimum basic medium of Eagle, and at the Ficoll-Paque higher slice.Sample is centrifugal, then lymphocyte is shifted out and is suspended in from water miscible Ficoll interface medium (15Mm HEPES, pH=7.4) in.With cell centrifugation, washing once suspends again again in the HEPES medium then.

By 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl bromination tetrazolium (tetrazolim) (MTT) is converted into purple first and estimates cytotoxicity.MTT is converted into dyestuff to carry out on porous plate.After the preparation, hepatomicrosome or lymphocyte separately or with concentration be the micromolar described test compound of 1-400 in the couveuse of humidification 37 ℃ hatch.After hatching, microsome/cell also suspends again with the washing of the albumin in the 5%HEPES-buffer medium.These microsome/cells are being hatched in the couveuse at humidification under 37 ℃ then.MTT with 125 micrograms after hatching joins in each hole.Make porous plate under 37 ℃, hatch and carry out centrifugal.After centrifugal, add 100 microlitre isopropyl alcohols, hatch the back and adopt automatic plate-reader to measure optical density.

The present invention is used for the chemical compound of the inventive method by the following detailed description of reference and the embodiment of compositions and effectiveness thereof further obtains explaining.To those skilled in the art, obviously can carry out manyly within category of the present invention, comprising modification on material and the method.5. embodiment 5.1 embodiment 1: the preparation of cis-Itraconazole and Itraconazole metabolite

Itraconazole can pass through Heeres, J. wait people's disclosed method in the article of J.Med.Chem.27:894-900 (1984) to synthesize, and (2R, 4S)-Itraconazole can pass through United States Patent (USP) the 5th, 474, disclosed method is synthesized in No. 997, and these two disclosed contents are used to prepare Itraconazole specially by reference herein.Prepare the hydroxyl Itraconazole similarly by reactions steps conventional in this area.The preparation of hydroxyl Itraconazole sees and for example is set forth in No. the 4th, 791,111, the United States Patent (USP) that this disclosed content is used to prepare the hydroxyl Itraconazole specially by reference herein.

Dioxolanes DTTT by literature method from R-3-tosyloxy (toxyloxy)-1,2-propylene glycol or S-3-tosyloxy-1, the 2-propylene glycol provides DTTT to prepare by the acidic catalyst ketal reaction.

In sulphur dioxide generation penta,, ring (dioxothiolane) was from the butanediol of suitable configuration, handled by adopting thionyl chloride, prepared by adopting sodium metaperiodate on the spot the cyclic sulfite of gained to be carried out oxidation in the presence of the tri-chlorination nail subsequently.

By United States Patent (USP) 4,267, in 179 the method for embodiment XVII prepared 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-piperazinyl] phenyl]-3H-1,2,4-triazole-3-ketone and Gao and Sharpless the method on J.Am.Chem.Soc.110:7538 (1988 year) of sulphur dioxide generation penta ring by revising adopt the hydrofining among the DMF to react in the presence of crown ether.Methoxyl group-the sulfate of gained is cracked into phenol-alcohol by heating at 100-110 ℃ of following HBr with 48%.

Make described tosylate and the described phenol-potassium hydroxide of alcohol in DMF in the presence of react to obtain product.

When needs R is sulfate, the order that can reset each step makes 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-piperazinyl] phenyl]-3H-1,2, the methoxyl group of 4-triazole-3-ketone carries out cracking before the sec-butyl side chain addition of remnants, and Dai Yixian adding dioxolanes DTTT, be sulphur dioxide generation penta ring then.

When needs R was phosphate, methoxyl group-sulfate can carry out the analog (wherein said phenol still keep methylated) of partial hydrolysis to obtain phenol-alcohol by the HBr with 48% under 45-50 ℃.Handle with dibenzyl diisopropylaminoethyl phosphate ester (phosphoramidite) and tert-butyl hydroperoxide according to the method for PCT application WO 94/17407 (incorporating this paper herein by reference into) then.Just obtain above-mentioned product after in the presence of palladium catalyst, making the benzyl protecting group cracking by hydrogenolysis.5.2 embodiment 2: antifungal activity Kirby-Bauer method of inspection

As above, prepare the active grown culture of Candida albicans, Cryptococcus histolyticus and saccharomyces cerevisiae described in No. 997 in the discussion of Van Cutsem with at United States Patent (USP) the 5th, 474.Culture is diluted to the 0.5McFarland standard, is coated onto then on 150 millimeters the SabouraudShi glucose agar plate.Adopt the disk liquor separator that paper disc (7 millimeters) is placed on the agar plate.Then each sample hydroxyl Itraconazole solution of 10 mg/ml of 10 microlitres is inhaled on the paper disc that moves on to separately.Each dish was hatched 16 hours under 30 ℃ then.Be that the inhibition zone is measured by unit then with the millimeter, gather as follows:

Chemical compound	Candida albicans	Cryptococcus histolyticus	Saccharomyces cerevisiae
Chemical compound	Candida albicans	Cryptococcus histolyticus	Saccharomyces cerevisiae	????A	????22	????28	????22
????B	????25	????25	????20	????A	????22	????28	????22
????B	????25	????25	????20	± Itraconazole	????17	????22	????15

Data represented inhibition zone (millimeter); A and B are hydroxyl Itraconazole sample.

The intravital activity of hydroxyl Itraconazole and derivant can compare the situation of the vaginal candidiasis of its anti-guinea pig skin candidiasis tested and rat.By adopting Candida albicans to bring out vaginal infection and assess the activity in vivo of these chemical compounds in vaginal candidiasis the Wistar of oophorectomize and hysterectomy rat (100 gram) (carrying out subcutaneous treatment with the estradiol undecylate in the 100 microgram Oleum sesami weekly).False estrous animal carries out intravaginal with the Candida albicans in the fixed concentration normal saline and infects.Fixed natural law after infection is estimated the contrast of infecting or curing by obtaining vaginal smear.Can be given in the to be assessed and medicine relatively that prevents or treat on the basis of mg/kg, judge its effectiveness by the ratio of negative animal in sum in each medicine group of comparison.In similar research, suppress the oidiomycotic activity of guinea pig skin for relatively providing the foundation people such as (, Chemotherapy, 17:392 (1972)) Van Cutsem.5.3 embodiment 3: the inhibition of Cytochrome P450

Carry out this research and suppress the degree of human-cytochrome P4503A4 (CYP3A4) to determine cis-Itraconazole and cis-hydroxyl Itraconazole.CYP3A4 relates to many medicines-medicine interphase interaction, and cis-Itraconazole and cis-hydroxyl Itraconazole have shown the probability of this medicine-medicine interphase interaction to the quantitative inhibition of CYP3A4.Model substrates testosterone and the deutero-CYP3A4 of cDNA-that employing is named in the microsome that human lymphoblastoid for h3A4v3 is preparation measure suppression ratio.Research design

This inhibition research comprises the inhibition concentration (IC that determines tester 50% ₅₀).(120 micromoles are about apparent K to the single testosterone concentration of duplicate test _mTwice) and the concentration (differing about 1/2 logarithm value) of ten testers.Analyze the metabolism situation of testosterone by the generation of 6 (β)-hydroxyl testosterone metabolite.HPLC separation through having absorbance detection is easy to this metabolite quantitative.Storage/the preparation of tester also adds Incubating Solution

Tester will at room temperature be stored down.Tester is dissolved in the ethanol to join in the Incubating Solution.For the concentration of all testers, the concentration of solvent will be constant.IC ₅₀Determine

The concentration of final test thing is 100,30,10,3,1,0.3,0.1,0.03,0.01,0.003 and 0 micromole.Each test concentrations will be tested in the double Incubating Solution according to following method: method

0.5 milliliter of reactant mixture that contains 0.7 mg/ml protein, 1.3 mM NADP+, 3.3 mM G-6-P esters, 0.4U/ milliliter G-6-P ester dehydrogenase, 3.3 mM magnesium chlorides and the testosterone of 120 micromoles in 100 mM potassium phosphates (pH=7.4) was hatched under 37 ℃ 30 minutes.Add known quantity as 11 (β)-hydroxyl testosterones of internal standard substance to proofread and correct the response rate during extracting.Described reactant mixture is extracted with 1 milliliter of dichloromethane.Extracting solution carries out drying and evaporates under vacuum through anhydrous magnesium sulfate.With sample dissolution in methanol and be injected in 4.6 * 250 millimeters 5u C18 HPLC posts and under 50 ℃, be that methanol is that 1 ml/min is separated with flow velocity with mobile phase.Retention time to 6 (β)-hydroxyls is about 6 minutes, is 8 minutes to the retention time of 11 (～)-hydroxyl, is 12 minutes to the retention time of testosterone.It is detected at the absorbance of 254 nanometers by product and internal standard substance, the absorbance correction extraction efficiency by adopting 11 (β)-hydroxyl peak is also compared with the absorbance of 6 (β)-hydroxyl testosterone standard curves and to be carried out quantitatively.Data report

For each tester, measured the concentration of 6 (β)-hydroxyl testosterone metabolite in each parallel Incubating Solution, calculate inhibition percent with respect to the solvent control thing.Calculate IC by linear interpolation ₅₀

Being used for the useful agents form that the inventive method gives described chemical compound can be described as follows: 5.4 embodiment, 4 capsules

A large amount of units capsule makes by filling standard two joint hard gelatin capsules, and each capsule is equipped with the Powdered active component of 1-100 milligram, 150 milligrams of lactose, 50 milligrams of celluloses and 6 milligrams of magnesium stearate.5.5 embodiment 5 Perles

The mixture of the active component of preparation in digestible oil such as Oleum Glycines, lecithin, Oleum Gossypii semen or olive oil, and be injected in the gelatin by positive displacement pump and form the Perle that contains 1-100 milligram active component.Washing capsule is also dry.5.6 embodiment 6 tablets

A large amount of tablets are prepared by conventional method, make that dosage unit is 1-100 milligram active component, 0.2 milligram of silica sol, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline Cellulose, 11 milligrams of starch and 98.8 milligrams of lactose.Can apply suitable coating to increase palatability or delayed absorption.

Except those contents of illustrating herein and describing, various modifications of the present invention (from above description) to those skilled in the art will be conspicuous.These modifications will belong within the category of appended claims.Above-mentioned all the most basic data of the present invention that make those skilled in the art can implement institute's claim that openly comprise.Because patent of being quoted from or disclosure can provide further useful data, so the material of these citations is all incorporated this paper herein by reference into.

Claims

1. treat or prevent the bacterial infection of people's general or locality, and avoid the method for the incident adverse side effect relevant simultaneously with taking the raceme Itraconazole, it comprises cis-hydroxyl Itraconazole or its pharmaceutically acceptable salt that gives described patient body and treat effective dose.

2. the process of claim 1 wherein that described disadvantageous side effect is QT interval prolongation, liver toxicity or passes through the Cytochrome P450 approach and suppress drug metabolism.

3. the process of claim 1 wherein the dosage of cis-hydroxyl Itraconazole be about 10 milligrams to about 500 mg/day.

4. the process of claim 1 wherein that the bacterial infection of being treated is erysipelothrix rhusiopathiae (Erysipelotric insidiosa), staphylococcus or Streptococcus.

5. the process of claim 1 wherein that the cis-hydroxyl Itraconazole of described amount or its pharmaceutically acceptable salt are with pharmaceutically acceptable carrier administration.

6. the process of claim 1 wherein that described infection is found among the central nervous system.

7. the method for claim 6, wherein said infection is found in brain.

8. treat or prevention people's general or locality infected by microbes, and avoid the method for the incident adverse side effect relevant simultaneously with taking Itraconazole, it comprises cis-hydroxyl Itraconazole or its pharmaceutically acceptable salt that gives described patient effective dose.

9. the method for claim 8, wherein said disadvantageous side effect for the QT interval prolong, hepatocyte toxic or suppress drug metabolism by the Cytochrome P450 approach.

10. the method for claim 8, wherein the consumption of cis-hydroxyl Itraconazole be about 1 milligram to about 1000 mg/day.

11. the method for claim 10, wherein the consumption of cis-hydroxyl Itraconazole be about 10 milligrams to about 500 mg/day.

12. the method for claim 8, the cis of wherein said amount-hydroxyl Itraconazole or its pharmaceutically acceptable salt are with pharmaceutically acceptable carrier administration.

13. the method for claim 8, wherein said infection is found among the central nervous system.

14. the method for claim 13, wherein said infection is found in brain.

15. the fungal infection of treatment or prevention people's locality or general, yeast infection and dermatophytosis infect, and avoid the method for the incident adverse side effect relevant simultaneously with taking Itraconazole, it comprises cis-hydroxyl Itraconazole or its pharmaceutically acceptable salt that gives described patient effective dose.

16. the method for claim 15, wherein said disadvantageous side effect for the QT interval prolong, hepatocyte toxic or suppress drug metabolism by the Cytochrome P450 approach.

17. the method for claim 15, wherein the consumption of cis-hydroxyl Itraconazole be about 1 milligram to about 1000 mg/day.

18. the method for claim 17, wherein the consumption of cis-hydroxyl Itraconazole be about 10 milligrams to about 500 mg/day.

19. the method for claim 15, wherein said fungal infection is various by aspergillosis, Aspergillus fumigatus, blastomycosis, Blastomyces dermatitidis, candida albicans disease, Candida albicans, Oidium tropicale, coccidioidomycosis, cryptococcosis, Cryptococcus histolyticus, Ctenomyces mentagrophytes, histoplasmosis, Sabouraudites lanosus, Mucor, tinea unguium, blastomyces brasiliensis, Phialophora verrucosa, pityrosporum ovale, Saprolegnia are various, Shen gram side spore, Sporothrix schenckii, Trichophyton mentagrophytes and trichophyton purpureatum are caused.

20. the method for claim 15, the cis of wherein said amount-hydroxyl Itraconazole or its pharmaceutically acceptable salt are with pharmaceutically acceptable carrier administration.

21. the method for claim 15, wherein said infection is found among the central nervous system.

22. the method for claim 21, wherein said infection is found in brain.

23. treatment or prevention people inflammation, and avoid the method for the incident adverse side effect relevant simultaneously with taking Itraconazole, it comprises cis-hydroxyl Itraconazole or its pharmaceutically acceptable salt with the treatment effective dose to described patient.

24. the method for claim 23, wherein the consumption of cis-hydroxyl Itraconazole be about 1 milligram to about 1000 mg/day.

25. the method for claim 24, wherein the consumption of cis-hydroxyl Itraconazole be about 10 milligrams to about 500 mg/day.

26. the method for claim 23, the cis of wherein said amount-hydroxyl Itraconazole or its pharmaceutically acceptable salt are with pharmaceutically acceptable carrier administration.

27. be used for the treatment of the Pharmaceutical composition that need carry out the people of anti-infective therapy, it comprises cis-hydroxyl Itraconazole or its pharmaceutically acceptable salt of pharmaceutically acceptable carrier and treatment effective dose.

28. the compositions of claim 27, wherein the consumption of cis-hydroxyl Itraconazole is about 50 milligrams to about 1200 milligrams.

29. the compositions of claim 27, wherein the consumption of cis-hydroxyl Itraconazole is about 100 milligrams to about 1000 milligrams.

30. the compositions of claim 27, wherein said compositions are applicable to oral, non-gastrointestinal or topical.

31. the method that treatment or prevention are infected in the central nervous system, it comprises the following formula: compound that gives the patient effective dose:

Wherein R be selected from hydrogen ,-P (O) (OH) ₂Or-SO ₃H, or its pharmaceutically acceptable salt.

32. the method for claim 31, wherein said infection are the infected by microbes that is selected from the secondary opportunistic pathogenesis of bacterial infection, fungal infection, yeast infection or dermatophytosis infection.

33. the method for claim 32, wherein said infection is found in brain.

34. treat or prevent the infection of philtrum, and avoid the method for disadvantageous drug interaction simultaneously, it comprises the following formula: compound for the treatment of effective dose: Wherein R be selected from hydrogen ,-P (O) (OH) ₂Or-SO ₃H, or its pharmaceutically acceptable salt.

35. the method that treatment or prevention people central nervous system's candidiasis infects, it comprises the following formula: compound that gives the patient effective dose:

36. the method for claim 35, wherein said infection is found in brain.

37. the method for claim 35 has wherein been avoided cis-hydroxyl Itraconazole and has been suppressed interaction between the medicine of Cytochrome P450.

38. the method for claim 35, wherein the consumption of cis-hydroxyl Itraconazole be about 1 milligram to about 1000 mg/day.