JPH03501967A - Fusidic acid useful in the treatment of AIDS - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Fusidic acid useful in the treatment of AIDS The present invention relates to fusidic acid and fusidic acid analogs, namely U.S. Pat. No. 06, No. 4100276, No. 4162259, No. 4315004, No. 4 No. 119717 and Vue Fora Daehne (W, von Daehne), V. O. Gottfredsen (W.

0, G oddtredsen) and P.R. Rasmurasen (P,R .

Rasmussen): r Structure-Activity Relation Sibs in fusic atrad-type antibiotics (S structure-Activity Re1ationships in F usidicAcid -Type Antibiotics) J, Atopansi What's in Applied? Microbiology (Advances in A) PI)lied Microbio-1ogy), Volume 25, pp. 95-146 ( fusidic acid analogues (hereinafter referred to as fusidic acid analogues) described in 1979) and their ARC (E) of their pharmaceutically acceptable salts and in vivo hydrolyzable esters. related to the prevention and treatment of AIDS-related syndromes) and AIDS (acquired immunodeficiency syndrome). bodies and their pharmaceutically acceptable salts and in vivo hydrolyzable esters, ARC and its use in the manufacture of drugs for the prevention or treatment of AIDS. Book The invention can be used for prophylaxis in HIV antibody positive persons or for the treatment of ARC and AIDS. A pharmaceutical composition used for treatment of patients, the composition comprising fusidic acid or its analogues. or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof. It also relates to pharmaceutical compositions containing together with acceptable non-toxic excipients.

Furthermore, the present invention provides a prophylactic method for HIV antibody positive persons, or an ARC or HIV antibody-positive person. fusidic acid or its analogs or its pharmaceutical comprising administering an acceptable salt or in vivo hydrolyzable ester. It also relates to methods.

Fusidic acid is an antibiotic with a narrow antibacterial spectrum, and is expressed by the following formula (1). It has the structure: Fusidic acid is derived from the fungus Fusidium Coccinelum (F usidium Cocc). ineum) and isolated in free acid or salt form (e.g. For example, US Patent No. 3,072,531 and British Patent No. 930,786; Ono Daene, Nis Sjaansen (S.

J. ahnsen), I. Kirk (1, Kirk), Earl Larsen (R.

L. Arsen) and H. Lorck: rBiotechno Science of Industrial Antibiotics (Biotech) -nology of Industrial Ant'1biotics)j , Fussic Assisted: Properties, Biosynthesis & Fell Maintenance (Fusidic Ac1d: Properties, Bi osynthesis andF ermentat 1on), E.G. ・Vandamme (E, J, V andamme), Marcel, Detsuka -(Marcel Decker), New York, 1984.427-449 Page: and V. O. Gottfredsen: Fussic Acid &. Sam Related Antibiotics (Fusidic acid a) nd some rated antibiotics), paper (D 1s sertation) l 967, University of Copenhagen).

Since its discovery in 1962, fusidic acid has been used to treat bacterial infections, especially staphylococcal infections. In treatment, it is widely used both systemically and locally and shows only a wide range of activity. Fushiji It is virtually non-toxic at normal therapeutic doses (up to 397 days). Fucidin for suppressing the emergence of acid-resistant mutants and/or to complement the antibacterial activity of fusidic acid. Fusidic acid is often combined with penicillins or other antibiotics to increase its effectiveness. used in combination (e.g. L.B., Garrod (L, P.).

Garrod), H, P, L ambert , F. O' Gardy and B.M.Water Worth (P.

M, Waterworth), Antibiotic and Chemose Antibiotics and Chemotherapy J, No. 5th edition, Churchill, Livingstone 5tone), 1981, pp. 220-225: and European Patent Application Publication No. 217 (See No. 580).

As part of the present invention, the following compound groups may be mentioned as examples of fusidic acid analogs. You can: A) Compounds of formula (II) disclosed in U.S. Pat. No. 4,060,606 thing 98.1 [Wherein, Ql and Q are HO or oxygen, A; Rufinyl group and R9 are straight chain or (branched alkyl group) having 1 to 8 carbon atoms, For example, methyl, ethyl, propyl, isobutyl, butyl, isobutyl, t-butyl, Lists the known isomers of pentyl, hexyl, heptyl and octyl. An alkyl group like this is a halogen atom or a hydroxy or alkyl group. cy, aralkyloxy, aryloxy, alkanoyloxy, aralkyl Oxy, aroyloxy, sulfhydryl, alkylthio, aralkylthio, a Lylthio, alkanoylthio, aroylthio, azide, nitro, cyano, thio Cyano, hydroxycarbonyl, alkyloxycarbonyl, aryloxycarbonyl Rubonyl, amino, alkylamino, dialkylamino, arylamino, alkylamino may be substituted with canoylamino and aroylamino groups; or R, is an alkenyl or alkynyl group having 2 to 6 carbon atoms, such as allyl, crotyl or propargyl, a cycloalkyl group having 3 to 7 carbon atoms in the ring, e.g. cyclo Propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Sometimes its mono- or dihalo, lower alkyl, lower alkoxy or hydro xy substituents, aralkyl, heterocycloalkyl or aryl groups such as pendyl, phenylethyl, phenyl or furfuryl; these groups are halogen nitro, lower alkyl, and hydroxyl groups are substituted with alkoxy groups. Also: or RI is a 5 or 6 member containing oxygen, sulfur or nitrogen atoms Heterocyclic groups of the ring, such as 2- or 3-pyrrolyl, 2- or 3-furyl, 2 -Likely 3-chenyl, 2-13- or 4-pyridyl, 2-14- or is 5-pyrimidinyl, 2- or 3-pyrazolyl, imidazolyl (e.g. l- methyl-2-imidazolyl), triazolyl (e.g. 5-methyl-1,2,4- triazol-3-yl), tetrazolyl (e.g. l-methyl-IH-tetrazo 5-methyl-1,3-yl), thiazolyl, thiadiazolyl (e.g. 5-methyl-1,3, 4-thiadiazol-2-yl). ] Dotted line between C-24 and C-25: Well, those carbon atoms are double bonds or single Indicates that they are connected.

B) U.S. Patent Nos. 4,100,276, 4,162,259 and 431.500 The compound disclosed in No. 4 and represented by the formula (III) [wherein Ql and Q2 are HO ... I or oxygen, A' is oxygen or sulfur, and Rlo has 1 to 1 carbon atoms 2 straight-chain or branched alkyl groups, such as methyl, ethyl, propyl, isopropyl Lopyl, butyl, isobutyl, t-butyl, and pentyl, hexyl, heptyl represents the known isomers of octyl, octyl and dodecyl; such alkyl groups , halogen atom or hydroxy, alkyloxy, aralkyloxy, ary alkanoyloxy, aralkayloxy, aroyloxy, sulfur Fuhydryl, alkylthio, aralkylthio, arylthio, alkanoylthio , aroylthio, azide, nitro, cyano, thiocyano, hydroxycarbonyl , alkyloxycarbonyl, aryloxycarbonyl, amino, alkyla Mino, dialkylamino, arylamino, alkanoylamino and aroyl It may be substituted with an amino group; or R1″ is an alkyl group having 3 to 6 carbon atoms. nyl or alkynyl groups, such as allyl, crotyl or propargyl, in alicyclic groups cycloalkyl group having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cycloalkyl Clopentyl, cyclohexyl, cycloheptyl, or its mono- or di- halo, lower alkyl, lower alkoxy or hydroxy substituted, aralkyl or is an aryl group such as benzyl, phenylethyl, phenyl, furfuryl or represents naphthyl, and these groups include /%rogen, lower alkyl, hydroxy or may be substituted with an alkoxy group; or R1' may be substituted with oxygen, sulfur or or a 5- or 6-membered heterocyclic group containing a nitrogen atom, such as a 2- or 3-pi lolyl, 2- or 3-furyl, 2- or 3-chenyl, 2-13-moshi 4-pyridyl, 2-14- or 5-pyrimidinyl, 2-like 3-pyridyl lazolyl, imidazolyl (e.g. !-methyl-2-imidazolyl), triazolyl (e.g. 5-methyl-1,2,4-triazol-3-yl), tetrazolyl (e.g. l-methyl-IH-tetrazol-5-yl), thiazolyl, thiadia Represents zolyl (e.g. 5-methyl-1,3,4-thiadiazol-2-yl).

] The dotted line between C-24 and C-25 indicates whether those carbon atoms are double bonds or single The asterisk at C-20 indicates that the compound has two diastereoisomers. Indicates that it exists as a mer form (all of which are included in the present invention).

C) Compound represented by formula (IV) disclosed in U.S. Pat. No. 4,119,717 HZ [In the formula, Q1' is oxygen, Z...1 or H...;, Z is hydroxyl group, halo Gen atoms, alkylsulfonyloxy or arylsulfonyloxy groups, e.g. For example, methanesulfonyloxy or p-trienesulfonyloxy, azide or or nitro group, Qt is oxygen or HO...I, and R is a straight group having 1 to 6 carbon atoms. Chain or branched alkyl groups, such as methyl, ethyl, propyl, isopropyl , butyl, isobutyl, t-butyl or pentyl and hexyl known isomers phenyl, or 5 or 5 containing silicon, oxygen and/or sulfur atoms Represents a 6-membered heterocyclic group, and these groups include halogen, nitro, lower alkyl or may be substituted with a lower alkoxy group. ]C-24 and C-25 The dotted line in between indicates that "lower" means 1 carbon atom unless otherwise specified. It means containing ~4 pieces.

Unless otherwise specified, an alkyl group preferably has 1 to 4 carbon atoms, and an alkanoyl group preferably has 1 (or 2) to 7 carbon atoms, and a preferable aryl group is phenyl and naphthyl. Preferred aralkyl, alkoxy, aralkyloxy, Aryloxy, alkanoyloxy, aralkayloxy, aroyloxy , alkylthio, aralkylthio, arylthio, alkanoylthio, aroyl Thio, alkoxycarbonyl, aryloxycarbonyl, alkylamino, di Alkylamino, arylamino, alkanoylamino, aroylamino groups, etc. , derived from the preferred alkyl, aryl and alkanoyl groups described above. child Any of these groups may be straight chain or branched.

Fusidic acid and a small number of related compounds have been Although it has been shown to have some in vitro activity against viruses [e.g. Br, J, Pharn+, Chemother, 1967.31.210 [See page 220], clinical use of fusidic acid or its analogs for viral diseases. Its effectiveness has not yet been shown.

Surprisingly, fusidic acid and fusidic acid analogues such as those mentioned above and their Pharmaceutically acceptable salts and in vivo hydrolyzable esters of retroviruses Treatment of ARC and AIDS caused by HIV (Human Immunodeficiency Virus) It was found that it has a floor effect.

Patients with ARC or AIDS are susceptible to many opportunistic infections; Because the immune system of such patients is impaired and therefore does not facilitate the elimination of pathogens, It is difficult to treat with conventional antibacterial therapy.

Of particular concern for these patients are the use of beta-lactam antibiotics and amino acids. Presence of intracellular microorganisms that cannot be reached by many known antibiotics such as noglycosides It is.

Fusidic acid is known to penetrate phagocytes and kill intracellular bacteria, so other Opportunistic use of fusidic acid sodium salt for its potential to support the action of antibiotics When administered to infected AIDS patients, fusidic acid was unexpectedly found to be effective against AIDS. When added to the treatment of patients with cancer, the antibacterial effects of well-known antibiotics cannot be explained alone. No significant improvement in general condition occurred. The present invention is designed to solve such unexpected occurrences. It is based on observation.

In view of these favorable clinical results, fusidic acid and its analogs have been tested in vitro against human immunodeficiency virus (HIV), the cause of HIV. Ta.

HIV is a T-4 helper phenotypically defined by the presence of CD4 molecules on its surface. A specific and selective subset of T-lymphocytes called inducer cells join to cut. cooperates with the class I major histocompatibility complex for antigen recognition The CD4 molecule used by human cells is also a receptor for viruses.

T-4 cells are primarily responsible for regulating virtually all immune functions in humans. , therefore,) (IV maximizes the immune system by reducing T-4 cells. can be damaged.

For in vitro testing of anti-HIV activity, a CD4 positive cell line was used. 3 types Cells with retrovirus isolates, namely CBL-1, ARV-2 and RF. To determine the concentration of fusidic acid required to prevent infection of the system. As a result, at a concentration of 60μ9/H, HIV prototype isolate CB of CD4-positive cell line can suppress infection by L-1 and inhibit cell line infection by ARV-2 and RF. It was found that a concentration of 100 μ9/R (l) was required to prevent infection.

Plasma concentrations of more than 100μ9/relative of the active ingredients of the invention are, for example, substantially non-toxic. can be easily achieved by oral or intravenous administration. white blood cells and The concentration of fusidic acid in lymphocytes is 7-10 times higher than in the surrounding system. Since it is known that HIV replication in humans can be inhibited at non-toxic doses, [A, F orsgren] and A. ・Be1ahsene (A, Be1ahsene): Scandinavian Journal・ Of Infectious Diseases (Scand, J, Infect, Dis、　r Antibiotic Accumulation in Hyuma Antipolymorphonuclea leukocytosis and lymphocytosis (Anti -biotic AccuII lulation in Human Poly morphonuclear Leu-cocytes and L lymph ocytes) J, 1985, Supplement 44, ■pages 6-23, ref.

Furthermore, analogues with in vitro activity against the retrovirus HIV have also been found. (See Table 1).

Thus, the present invention provides fusidic acid and its analogs and their pharmaceutically acceptable Preparation of acceptable salts and in vivo hydrolysable esters for HIV antibody positive individuals for use in the manufacture of drugs for protection or for the treatment of patients with ARC or AIDS. related.

Furthermore, the present invention provides a method for preventing or treating ARC and AIDS, comprising: Acids or analogs thereof or their pharmaceutically acceptable salts or in vivo hydrolysis administering the degradable ester to a human in need of such treatment. .

In addition, the present invention provides prophylactic or ARC for HIV antibody positive persons and AIDS prevention. A pharmaceutical composition for the treatment of a patient, comprising: fusidic acid or an analogue thereof; pharmaceutically acceptable salts or in vivo hydrolyzable esters. The present invention also relates to compositions containing the same with non-toxic excipients.

The pharmaceutical compositions of the invention typically contain the active ingredient (fusidic acid or its analogs or its derivatives). (a pharmaceutically acceptable salt or in vivo hydrolyzable ester) or prepared by combining with further pharmaceutically acceptable non-toxic excipients. Ru.

Examples of pharmaceutically acceptable salts include alkali metals, alkaline earth metals, amines and and fusidates with alkanolamines; e.g., water-soluble sodium salts, potassium ammonium salt, triethylamine salt, piperidine salt, morpholine salt, Cyclohexylamine and jetanolamine salts and slightly water-soluble Lucium salt, magnesium salt, 5yI11-dibenzylethylenediamine salt, base and procaine salts. other suitable salt For example, pyrrolidine, piperazine, guanidine, methylamine, ethylamine , benzylamine or similar unsubstituted or substituted amines, choline and its salts with quaternary amines, such as derivatives, as well as basic antibiotics, e.g. cids and ansamycines, e.g. Salt with Shirin.

Examples of in vivo hydrolyzable ester groups are: C3-C8 alkano yloxymethyl, 1-(alkanoyloxy)-ethyl having 4 to 9 carbon atoms, carbon Alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxymethyl having 4 to 7 carbon atoms) cyclocarbonyloxy)-ethyl and α-aminoalkanoyl radicals having 2 to 6 carbon atoms. oxymethyl.

Other preferred esters are lactonyl esters, such as 3-phthalidyl, 4-phthalidyl, Rotonolactonyl or γ-butyrolactone-4-yl ester.

Methoxymethyl, cyanomethyl, or mono- or dialkyl substituted amino acids lukyl esters, such as 3-diethylaminoethyl, 2-diethylaminoethyl , or 3-dimethylaminopropyl ester are also included within the scope of the present invention.

A pharmaceutically acceptable excipient is one that is acceptable for administration to the patient in terms of toxicity and that is compatible with the active compound. Any carrier, diluent, filler, binder or other carrier that does not materially interfere with the administration of the It should be interpreted broadly to include substances, such as inert drug excipients that facilitate compounding. be.

Depending on the method of administration, the compositions of the invention can be administered in solid, semi-solid, or liquid dosage forms. For example, tablets, capsules, sterile powders for reconstitution prior to parenteral administration, fully opened, round Forms of medicines, solutions, suspensions, etc., preferably units of precise dosage suitable for single administration It may be in dosage form. Such unit dosage forms have a dosage of 0.025 per dosage unit. It is preferred to contain an amount of active ingredient of ~1 g.

For solid compositions, conventional non-toxic solid excipients include, for example, pharmaceutical grade mannitol. Le, lactose, starch, magnesium stearate, sodium saccharin , talc, cellulose, glucose, sucrose, magnesium carbonate, etc.

The active ingredient may be a polyalkylene glycol such as propylene glycol. It can be prepared completely using silica as a carrier. The pharmaceutically acceptable liquid composition comprises: For example, the active compounds and any pharmaceutical adjuvants may be combined in water, physiological saline, aqueous dextrose, etc. Dissolve, disperse, etc. in a ζ carrier such as trose, glycerol, ethanol, etc. It can be prepared by forming a solution or suspension. Medications to be administered, if necessary. The composition may contain non-toxic adjuvants such as moisturizers, emulsifiers, pH buffers, etc., e.g. vinegar. sodium acid, sorbitan monolaurate, triethanolamine sodium acetate It may also contain compounds such as triethanolamine oleate, triethanolamine oleate, and the like. Such dosage forms Actual preparation methods are known to those skilled in the art or are available from, for example, Remington's Pharma. Ceutical Sciences (Reming-ton’s Pharmac eutical 5 sciences), Hook 0 Publishing Co., Ltd. (Mack P Publishing Company), Easton, Pennsylvania, 15th edition, It can be known from 1975.

For oral administration, avoid possible local irritation caused by the dose of fusidic acid used. It is preferable to use formulations that disintegrate quickly. Particularly preferred products of this kind The agent is a film coating containing the following ingredients: Active ingredient 40-60% by weight Crospovidone 5-20% by weight auxiliary agent Total amount 10 0% by weight (For example, fillers like lactose and microcrystalline cellulose: gelatin and Binders like polyvinylpyrrolidone Lubricants like Nisilica: talc and steel lubricants such as magnesium phosphate; disintegrants; preservatives; fragrances, etc.) The film coating consists of, for example, hydroxypropyl methylcellulose. , and may contain colorants such as titanium dioxide.

Film-coated tablets disintegrate quickly and provide good elasticity without causing local irritation. Indicates IO availability.

Administration of the active ingredient of the present invention and the pharmaceutical composition may be carried out using a method for administering an antiviral agent. It may be performed by a method that allows for deviation. Such methods include oral, parenteral and other systemic administration. Parenteral administration is typically administered by intravenous injection or infusion. It is characterized as.

The amount of active ingredient administered will depend on the recipient, the severity of the condition, the method of administration and the prescribing physician. Naturally, it depends on the judgment of the person. However, the daily dose is usually 5-75 x 9/kg body weight. , preferably within the range of 10 to 50 rrg/kg body weight, for example once a day. or administered orally multiple times, preferably 1 to 3 times, or by continuous infusion. .

Treatment with the active ingredients of the present invention can be used as antibacterial, antituberculous, antifungal, anthelmintic or antiviral agents. Advantageous in combination with other treatments such as laxatives and/or immunomodulators It is. Combination treatments involve the use of drugs individually or as fixed combinations. This can be done by administering.

Examples of antimicrobial agents used in such combination treatments include: can be -lactam antibiotics, e.g.: (i) Penicillins and their prodrugs, such as benzylpenicillin, Phenoxymethylpenicillin, methicillin, nafcillin, oxacillin, black sacillin, dicloxacillin, flucloxacillin, ampicillin, epicillin , amoxicillin, hetacillin, bivanpicillin, bacampicillin, cilinpicillin Lin, lenampicillin, carbenicillin, cal benicillin, calindacillin, ticarcillin, ampicillin, mezlocillin, pi perazillin, ampicillin, ampicillin (aspoxicillin), sul benicillin, temoillin, formidacillin midacillin; BRL36650), mecillinum [anginocillin (a mdinocillin) 3, Bibmecillinum, Bakumecillinum, Augmench augments in and sultamicilli n): (ii) Cephalosporins and their prodrugs, e.g. loglycine, cephalothin, cephaloridine, cefazolin, cephalothin, cephalothin, Falexin, cefrazine, cefamandole, cefonicito, cefocidime, Cefuroxime, cefuroxime axetil, cephalexin, cephalexin, Cefocidime, ceftriaxone, cefmetuxime , cefuozidime, cefviramide, cefvinazole (c +Jpinazole), cefpiramide, cephalotherapy Chin (cefpiro+ne), cefminox (cer-minoX), cef Zonam (c+Juzonam); cefepime (cefepime: BMY) 28142), cefaclor, cefadroxil, cef Osidim, cefonicito (cefixiIIle), cefmetazole (cere) tamet), ceftetrame, cefteram pivoxi le (cefterampivoxi+), 5CH39720 (7432-S), Cefaxin, cefmetazole, cefocidime (cefotetan), cefubi Lamid (cefbu-perazone), maxalactam (maxalact am) and flomoxef (No-a+oxef; 6315-S): (iii) Monobactams (@in□bactams) and their prodrugs such as azthreonam, carmonum monam), tigeminam and vilazmonam (pi). razmonam): and (iv) carbapenems (carbapenem s) and penems and their prodrugs, e.g. imipenem, FCE2210L 5CH29482 and 5C H38343゜Tetracycline antibiotics, e.g. tetracycline, chlorothene tracycline, oxytetracycline, loritetracycline, demeclosa Iclin, rimcycline, methacycline, chromocycline, cloxycycline Clin (c Ioxycyc l 1ne) and minocycline: Macrolide and lincosamide antibiotics, e.g. Erythromycin and its esters, oleamidomycin, josamycin , rosalamycin (rosaraa+1ycin) ~ spiramycin roxito Romycin (roxithros+ycin), lincomycin and syrin and rifabutin; quinolone anti- Biological substances such as nalidixic acid, norfloxacin, ofloxacin, ciprofloxacin oxacin), enoxacin (enoxacin), fleroxacin (fl roxacin), dimethoxin (dirloxacin), vilfloxacin (pirfloxacin) and pefloxacin (pefloxacin) Aminoglycoside antibiotics, such as gentamicin, kanamycin, tobramycin Syn, Dibekacin, Abikamycin, Streptomycin amikacin, spectinomycin, butyrosin, sissosycin, framycetin and neomycin : Diaminopyrimidines, such as trimethoprim and tetracyline (tetr oxaprim); Sulfonamides, such as sulfamethizole, sulfadiazine, sulfadiazine Methoxine, sulfamethoxypyridazine and phthalylsulfathiazole; and Other antibiotics, such as chloramphenicol, oly-myxi n), deptomycin (LY 146032), bobiocin, vancomycin, teicoplanin and fosfomycin.

Examples of antifungal agents used in combination treatments include Amphotericin B1 Nysk Chin, griseofulvin, flucytosine, miconazole, clotrimazole eco Nazole and Ketoconazole.

Examples of anthelmintics used in combination treatments include metronidazole, tinidazole chloroquine, levamisole and pentamidine.

Examples of anti-tuberculous drugs used in combination treatment include isoniacyto, ethambutose. p-aminosalicylic acid, vilacinamide and dapsone. Can be mentioned.

Examples of antivirals used in combination treatments include acyclovir, amphotene, Ricin B methyl ester, glycyrrhizin, ribavirin, amantidine (ama ntidine), foscarnet, ganciclovir ), eflornithine (ef1ornithine) and desciclovir (d esciclivir).

Examples of immunomodulators used in combination treatments include α-interferon, β- Interferon, cyclosporine, interleukin 2, isoniacyto, crayon stin, lentinan, muramyl tripeptide and penicillamine.

An example of the medical history of an AIDS patient treated with fusidic acid is given below: Hepatitis (HBsAG) A 58-year-old male patient with a history of recurrent seborrheic dermatitis was diagnosed in 1984. Until then, he had been in good health, but in 1984 he visited the hospital complaining of malaise, fever, and weight loss. As a result of L0 examination, this patient was found to have systemic lymph nodes. This too The patient was HIV positive by ELISA and Western blot and had T helper lymphocytes. The lymphocyte count was normal, but the patient was allergic or nonspecifically mitogenic.

She remained stable without further deterioration until 1986, when she started to lose weight even more. I had some diarrhea. Gastroenterological examination revealed atrophic gastritis, B12 malabsorption, Candida esophagitis, colon amoeba, Entoairoeba hartmanii, Amoeba amoeba, Iodoamoeba butcherii and Anthelminthica were detected. Rin Mycobacterium tuberculosis from both stool and bleeding after acid-fast bacteria were tested in the node biopsy. was multiplied. The patient was given isoniacit, ethambutol and liambicin. The animal was given deworming treatment and topical antifungal treatment. 6 weeks after treatment, His condition did not improve, and he continued to lose weight (16 kg since admission).

At this point, administration of fusidic acid sodium salt (500!+9.3 times a day, orally) was started. Added to treatment. Two weeks after initiation, the patient became afebrile, began to gain weight, and I was able to undergo a urethral prostatectomy and have returned to work and have been healthy ever since. be. After 2 months, the weight increased by 10 kg.

The following examples are intended to illustrate the invention and are intended to reduce or reduce the scope of the invention. or should not be construed as limiting the scope of the invention.

Example 1 capsules Sodium fusidate 250g Polyvidon 0g Magnesium stearate 5g Sodium fusidate in polyvidone solution in ethanol/methylene chloride (1:9) Moisten the granules and dry the granules at 35°C. Sieve the granules through a 0 and 6 mm sieve. Filter and mix with magnesium stearate.

Fill a No. 0 hard gelatin capsule with the granules at a filling weight of 265λ9 to make approximately 1000 capsules. Get a cell.

Example 2 tablet Sodium fusidate 200g Bolividone 10g Crospovidone 50g Lactose 210g Talc 25g Magnesium stearate 5g Sodium fusidate in polyvidone solution in ethanol/methylene chloride (1:9) Moisten the granules and dry the granules at 35°C. Sieve the granules through a 1mm sieve and Mix with Rospovidone, Lactose, Talc and Magnesium Stearate . 12III! 100 tablets of 50019 each using a tablet press with a circular punch Compress 0[ into tablets.

Example 3 tablet Sodium fusidate 250g Bolividone 12.5g Crospovidone 50g Talc 36g Colloidal silica 5g Microcrystalline cellulose 72g Lactose 72g Gelatin 0.4g Magnesium stearate 2g Hydroxypropyl methylcellulose 8g Titanium dioxide 0.5g Sodium fusidic acid solution in ethanol/methylene chloride (1:9) Moisten the granules and dry the granules at 35°C. The granules are sieved through a lem sieve.

Lactose was granulated with gelatin dissolved in water, dried at 60°C, and the granules were 1++i sieve through a n sieve. The granules are mixed with crospovidone, talc, silica, cellulose and and magnesium stearate. 7.8X16mm oval punched lock Compress 1000 tablets of 5006 each using a tablet press. equal amount of ethanol and prepared from hydroxypropyl methylcellulose and titanium dioxide in water The tablets are film coated with the solution in a fluidized bed coater.

Example 4 solution for injection Prepare a solution for intravenous injection by dissolving the following dry product in a solvent at the time of use: dry matter Sodium fusidate 1000g Sodium fusidate Ig was aseptically dry-filled into each sterile vial and sealed with a rubber stopper. and seal with an aluminum cap.

solvent Citric acid 20g Sodium phosphate 390g Water for injection: 20Q Dissolve citric acid and sodium phosphate in water for injection.

Filter the solution with a 0.2 μm membrane filter and add 20 ml to each vial. put in. Seal the vial with a rubber stopper and aluminum cap. Finally, melt Sterilize the solution in an autoclave at 121"C for 15 minutes.

Example 5 solution for injection Prepare a solution for intravenous injection by dissolving the following dry product in a solvent at the time of use: dry matter Sodium 16-diacetoxy-16β-acetylthiofusidate (VD146 0 sodium) 1040gVD1460 sodium 1.04g in each sterile vial Dry fill aseptically and seal with rubber stoppers and aluminum caps.

solvent Citric acid 20g Sodium phosphate 390g Water for injection 2012 Dissolve citric acid and sodium phosphate in water for injection and add 20ml to each vial. put it in the file.

Seal the vial with a rubber stopper and aluminum cap. Finally, add the solution to 12 Sterilize in an autoclave at 1'C for 15 minutes.

Example 6 capsules Sodium 16-diacetoxy-16β-benzoylthiofusidate (VD15 46 Sodium) 250g Cornstarch 25g Polyvidone 8g Magnesium stearate 5g VD1546 sodium is mixed with cornstarch and the powder is mixed with an equal amount of ethanol. water and a solution of boribidone in deionized water.

The granules were dried at 40°C, sieved through a 0.6 Dragon sieve, and mixed with magnesium stearate. Mix. Fill a No. 0 hard gelatin capsule with the granules at a filling weight of 28,819, Approximately 1000 capsules are obtained.

Example 7 tablet 3α, 11α-2 bitroxy-16β-isoprovir thiofucida 13 (17), 24-diene-21-acid (PR1089) 400g Cornstarch 200g Methylcellulose 15cps 30g Crospovidone 30g Magnesium stearate 5g Mix PR+089 with cornstarch.

The powder is moistened with an aqueous solution of methylcellulose and the granules are dried at 50°C.

The granules were sieved through a 1 mm sieve, and crospovidone, magnesium stearate, and mix with chlorine and silicon dioxide. 13.5mmmm circular bunch tablet press 1000 tablets of each 70029 were compressed using the same method.

Example 8 tablet Fusidic acid 250g Methylcellulose 15cps 15g Cornstarch 30g Microcrystalline cellulose 70g Mix fusidic acid, rifampicillin and corn starch, and dehydrate the powder. Wet with methylcellulose dissolved in ionized water.

Dry the wet mass at 45° C. and sieve the granules through 1, 2 m+n sieves.

The granules are mixed with cornstarch, microcrystalline cellulose, talc and magnesium stearate. Mix with um.

Using a tablet press with a 1010X18 oval punch, 10 tablets of 755x9 each Compress 00 tablets.

National AT [inspection report] 1mv floor mm-^5ellc++lucidN・pmT/Tp RR/(1(M;Go -:)--wgal h**bt*bwm, :'C'r/EP 88100 660 International Search Report εP 8800660 Note table Hei 3-501967 (14) ・Car-3500 Berlese, Nerle Benguet

Claims (18)

[Claims] 1. A pharmaceutical composition for the prevention and treatment of AIDS-related syndromes and AIDS, comprising: as an active ingredient a) Fusidic acid and its pharmaceutically acceptable salts and in vivo hydrolyzable esters Tell; b) Formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, Q1 and Q2 are ▲mathematical formulas, There are chemical formulas, tables, etc. ▼ or oxygen, A is oxygen or sulfur or sulfur Nyl group and R1 are straight chain or branched alkyl groups having 1 to 8 carbon atoms, and isomers. and such an alkyl group contains one or more halogen atoms or hydrogen atoms. droxy, alkoxy, aralkyloxy, aryloxy, alkanoyloxy cy, alkanoyloxy, aroyloxy, sulfhydryl, alkylthio, alkyloxy Ralkylthio, arylthio, alkanoylthio, aroylthio, azide, nito b, cyano, thiocyano, hydroxycarbonyl, alkyloxycarbonyl, Aryloxycarbonyl, amino, alkylamino, dialkylamino, aryl be substituted with aryamino, alkanoylamino and aroylamino groups or Rl is an alkenyl or alkynyl group having 2 to 6 carbon atoms, in an alicyclic group; cycloalkyl group having 3 to 7 carbon atoms, or its mono- or dihalo, alkyl group alkyl, alkoxy or hydroxy substituted, aralkyl, heterocycloalkyl or aryl Represents lyl groups, these groups contain one or more halogen, nitro, alkyl may be substituted with a methyl, hydroxy or alkoxy group; or R 1 represents a 5- or 6-membered heterocyclic group containing oxygen, sulfur or nitrogen atom. ] and its pharmaceutically acceptable salts and in vivo hydrolysis sexual ester; c) Formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, Q1 and Q2 are ▲Mathematical formulas , chemical formulas, tables, etc. ▼ or oxygen, A' is oxygen or sulfur, and R 1' represents a straight chain or branched alkyl group having 1 to 12 carbon atoms; Alkyl groups include one or more halogen atoms or hydroxy, alkyl cy, aralkyloxy, aryloxy, alkanoyloxy, alkanoyloxy xy, aroyloxy, sulfhydryl, alkylthio, aralkylthio, ali althio, alkanoylthio, aroylthio, azide, nitro, cyano, thioshi Ano, hydroxycarbonyl, alkyloxycarbonyl, aryloxycar Bonyl, amino, alkylamino, dialkylamino, arylamino, alkali May be substituted with noylamino and aroylamino groups; or R 1' is an alkenyl or alkynyl group having 3 to 6 carbon atoms, or an alicyclic group having 3 to 7 carbon atoms. Cycloalkyl group, or its mono- or dihalo, alkyl, alkoxy or or hydroxy-substituted, aralkyl or aryl group, and these groups represent 1 Substituted with one or more halogen, alkyl, hydroxy or alkoxy groups or R1' may contain an oxygen, sulfur or nitrogen atom. represents a 5- or 6-membered heterocyclic group. ] Compounds represented by; and their pharmaceutically acceptable salts and in vivo hydrolyzability ester; and d) Formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) [In the formula, Q1' is oxygen or ▲Mathematical formula , there are chemical formulas, tables, etc. ▼ or ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼, Z is Hydroxyl group, halogen atom, alkylsulfonyloxy or arylsulfonyl Oxy group, azide or nitro group, Q2 is oxygen or HO...H, and R1'' is Straight chain or branched alkyl group having 1 to 6 carbon atoms, phenyl, nitrogen, oxygen or represents a 5- or 6-membered heterocyclic group containing a sulfur atom and/or a sulfur atom; The group can be one or more halogen, nitro, alkyl or alkoxy groups. Sometimes it is replaced. ] Compounds represented by; and their pharmaceutically acceptable salts and in vivo hydrolyzability ester an effective amount of at least one compound selected from the group consisting of one or more A pharmaceutical composition containing the above pharmaceutically acceptable non-toxic excipients. 2. The composition of claim 1 in the form of a sterile powder for reconstitution prior to parenteral administration. . 3. 2. The composition of claim 1 in the form of an aqueous suspension or solution. 4. A composition according to claim 1 in the form of a tablet or capsule. 5. The compound according to claim 1 is contained in an amount of 0.025 to 1 g per dosage unit. A compound according to claim 4. 6. Fusidic acid or its pharmaceutically acceptable salt or in vivo hydrolyzable salt 2. A composition according to claim 1, containing Stell. 7.16-deacetoxy-16β-acetylthiofushidic acid or its pharmaceutical A set according to claim 1 containing an acceptable salt or in vivo hydrolysable ester. A product. 8.16-deacetoxy-16β-benzoylthiofushidic acid or its pharmaceutical of claim 1 containing a salt or an in vivo hydrolysable ester that is acceptable for Composition. 9.3α,11α-dihydroxy-16β-isopropylthiofucida-17(7 ), 24-dienoic acid-21 or a pharmaceutically acceptable salt thereof or in vivo processing. The composition according to claim 1, containing a water-degradable ester. 10. Film coating containing the following ingredients in the stated amounts (relative to total weight): Gu tablet; Fusidic acid or a pharmaceutically acceptable salt thereof 40-60% by weight Crospovidone 5 ~20% by weight The total amount of excipients is 100% by weight. 11. As an active ingredient in the prevention and treatment of AIDS-related syndromes and AIDS A compound according to claim 1 for use. 12. As an active ingredient in the prevention and treatment of AIDS-related syndromes and AIDS Fusidic acid used and its pharmaceutically acceptable salts and in vivo hydrolyzability ester. 13. In the production of AIDS-related syndromes and drugs for the prevention and treatment of AIDS. Use of a compound according to claim 1 as an active ingredient. 14. AIDS-related syndromes and people who are at risk of or have AIDS. 2. A method of treating a patient who is suffering from cancer, comprising using as the active ingredient an effective amount of a compound according to claim 1. A method comprising administering to a patient. 15. Includes AIDS-related syndromes and preventive measures for people at risk of contracting AIDS. 15. The method of claim 14. 16. A contract that involves the treatment of AIDS-related syndromes and patients suffering from AIDS. The method according to claim 14. 17. The compound according to claim 1 as an active ingredient is combined with one or more antibacterial agents. in combination with drugs, antituberculous drugs, antifungal drugs, anthelmintic drugs, antiviral drugs and/or immunomodulators. 15. The method of claim 14, comprising administering in combination. 18. The compound according to claim 1 as an active ingredient can be used as an asamicin antibiotic, e.g. 15. For example, comprising administering in combination with rifampicillin. the method of.