BG62035B1 - New therapeutical application of fluoroquinolone derivatives - Google Patents

Abstract

Treatment or prevention of nephrotic syndromes is effected bythe administration of a derivative of the class offluoroquinolones having a general formulathere R1 is alkyl radical having 1 to 4 carbon atoms, fluorethyl,cyclopropyl, methylamino or difluorophenyl, X is nitrogen atom orgroup =CR7-, where R7 is H, Cl or F or R7 forms with radical R1and C atoms with which they are bound, heterocycle having sixatoms, substituted by methyl and containing eventually oxygen orsulphur atom, R2 is H, or can be amino radical if R7 is F and R3is H, radical 2,8-diazob1cyclo/4.3.0/non-8-yl or radical having astructure where R4, R5 and R6 are identical or different and are Hor methyl, or by administration of its pharmaceutical acceptablesalt.

Description

The invention relates to a new therapeutic use of fluoroquinolone derivatives for the treatment of nephrotic syndrome

T ² 0 A COOH R ₃ X and | / I / * 1 in which R, is an alkyl radical containing

BACKGROUND OF THE INVENTION

Nephrotic syndrome is a severe renal impairment characterized by hypoalbuminemia and significant proteinuria (mainly albuminuria) as well as the onset of edema syndrome. It can sometimes lead to the need for an extrarenal purification of 20 blood, to a kidney transplant, or it can be a deadly complication, especially in children.

Typically, nephrotic syndrome is treated with corticotherapy or with medications such as azathiopyrin, cyclosporin A, or chlorambucil. This long-term treatment (6 months to 1 year on average) may be accompanied by adverse secondary effects of corticosteroids or lead to toxic haematological, hepatic, gonadal or renal types. Recurrences are common and warrant the prescription of repeated and prolonged treatment. However, a number of nephrotic syndromes resist any treatment. Many cases evolve to extrarenal complications and to chronic renal failure.

The therapeutic class of fluoroquinolones is widely known and used for antibacterial treatment. The cited literature describes derivatives of the invention used as antibacterial agents: BE

870 576, US 4 448 962, DE 3 142 854, EP 047 45 005, 206 283, BE 887 574, EP 221 463, 140 116,

131 839, 154 780, 078 362, 310 849, 520 240, US 4 499 091, 4 704 459, 4 795 751, 4 668 784.

SUMMARY OF THE INVENTION 50

It has now been found that derivatives of clause 1 to 4 carbon atoms, fluoroethyl, cyclopropyl, methylamino or difluorophenyl, X represents a nitrogen atom or a group = CR ₇ - in which R ₇ is a hydrogen atom, chlorine or fluorine or else R ₇ forms, with the radical R [and the atoms to which they are attached, a six-atom heterocycle substituted with a methyl radical and optionally containing an oxygen or sulfur atom; R ₂ is a hydrogen atom or may represent an amino radical if R ₇ is a fluorine atom and R ₃ is a hydrogen atom, a 2,8-diazobicyclo / 4.3.0 / non-8-yl radical or a radical of structure

wherein R ₄ , R ₅ and R ₆ are identical or different and represent hydrogen atoms or methyl radicals, or their pharmaceutically acceptable salts, have an effect on the nephrotic syndrome, thereby remission and cure of this disease.

Of the quinolones cited herein are particularly interesting are pefloxacin, sparfloxacin, ciprofloxacin, ofloxacin, levofloxacin, enoxacin, norfloxacin, phleroxacin, lomefloxacin, temafloxacin, amifloxacin, 62 flufacin, flufacin18 rufluxacin, flufacin18 rufluxacin, rufluxacin

Application of the invention

The activity of the products of general formula I is as follows.

Patients afflicted with nephrotic syndrome showing proteinuria of 2.5 g to 12.5 g per 24 h and plasma albumin levels reaching 22 to 42 g / l on day D _o take day _{1 of} pef.toxacin / dihydro-1,4 ethyl-1 fluoro-6 (methyl-4-piperazinyl) -7 oxo-4-hex: -: oline-carboxylic-3 acid / 2-fold dose of 400 mg orally. Daily treatment in this way lasts for 2 to 5 weeks. Proteinuria was measured on day 15 and day 30, respectively. Albuminemia was measured on day 30. The results are shown in Table 1.

Table 1

Sick # Proteinuria B Up to g / 24 h Plasma Albumin In To g / 1 Duration of treatment, weeks Proteinuria D, 5> g / 24 h Proteinuria In Jo 'g / 24 h Plasma albumin B Zo g / i Relapse 1 7 41,6 2 0.20 0.20 imm. 3 months 2 5.5 28.5 4 1.64 0.34 36 no 3 9.7 22 4 imm. 1.32 24 no 4 2.8 26 4 0.20 0.20 imm. no 5 12 25 4 0.35 0.54 33 for 2 months 6 6.5 imm. 5 1.17 0.20 28 no 7 7 26 2 1.82 0.60 35,3 6 months 8 12.5 24 4 9 1,75 23.6 -

The results show that remission occurs between days 8 and 15 of treatment when proteinuria disappears over a 3-day period.

Patients who relapse are re-treated with 400 mg twice daily pefloxacin. The results are shown in Table 2.

Table 2

Sick # Duration of treatment, weeks The result 1 4 remission 5 4 remission 7 4 remission

The recurrence-free and treatment-free time was 4 years for the first treated patient <not presented in Table 1). A remission of 12 months was observed in one patient treated after the second relapse (patient # 1). One patient (No. 7) underwent renal transplantation and showed relapse of nephrotic syndrome with small glomerular lesions <SN-L GM) from E ₃ . was treated for 15 days, starting on day 17 after grafting with pefloxacin, then for 1 month after 7 months of grafting, and remission was observed without relapse of 1 year and 3 months with proteinuria ranging from 0.4 to 25 0.6 g / 24 h.

In a similar protocol, the other fluoroquinolones of general formula I show similar results.

The invention also relates to a medicament for the treatment of nephrotic syndromes containing at least one product of general formula I, optionally in the form of a salt, in its pure form or in the form of a pharmaceutical composition together with one or more diluents and / or additives, which are compatible and pharmaceutically acceptable. These formulations may be administered orally or parenterally.

Tablets, pills, gelatin capsules, powders or granules may be used as solid compositions for oral administration. In these compositions, the product which is active according to the invention is mixed with one or more diluents or inert additives such as sucrose, lactose or starch. These compositions may contain substances other than diluents, for example lubricants such as magnesium stearate.

As liquid compositions for oral administration 50, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or paraffin oil may be used. These compositions may also contain substances other than diluents, for example wetting, sweetening or flavoring agents.

The compositions for parenteral administration may be sterile aqueous or non-aqueous solutions, suspensions or emulsions. Propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate, may be used as the solvent or carrier. These compositions may also contain additives, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be accomplished in various ways, for example with a bacteriological filter, by irradiation or by heating. They may also be prepared in the form of solid sterile compositions which may be dissolved at the time of use in sterile water or in any other sterile injectable medium.

Compositions containing fluoroquinolone derivatives may be administered for therapeutic or preventative purposes by persons presenting with cases of nephrotic syndrome, such as idiopathic nephrotic syndrome with minor glomerular lesions, glomerulonephritis extramembranous, or idioponylmericloromerilomeric.

According to the invention, the physician determines the dosage that he or she considers most appropriate for preventive or curative treatment, depending on age, weight, degree of syndrome, and other factors typical of the person being treated. As an example, the dose can be between 400 mg 3 times a week and 800 mg daily for 15 days to 1 month. However, daily doses may be higher, if necessary, with daily doses up to 5 g per adult.

Examples of carrying out the invention

The following examples illustrate the compositions of the invention for the treatment of nephrotic syndrome.

Example 1: 400 mg tablets are prepared which have the following composition: pefloxacin in the form of mesylate dihydrate - 400 mg, excipient - kernel: cereal starch, gelatin, talc, magnesium stearate, sodium carboxymethyl starch as needed for the nucleus , shell - hydroxypropyl methylcellulose, ethylcellulose, dibutylsebacate, titanium oxide, talc, polyoxyethylene glycol 6000.

Claims (3)

A method for treating or preventing nephrotic syndromes, characterized in that it is derived from a class of fluoroquinolones corresponding to of a general formula I ² 0 II ή JCJ " x 1 * 1 wherein R, is alkyl radical, containing 1 to 4 carbon atoms, fluoroethyl, cyclopropyl, methylamino or difluorophenyl, X represents a nitrogen atom or a group = CR, - in which R is a hydrogen atom of chlorine or fluorine or else R _? forms with the radical R _t and the atoms to which they are attached a six-atom heterocycle substituted with a methyl radical and optionally containing an oxygen or sulfur atom, R 1 is a hydrogen atom or may represent an amino radical if R ₇ is a fluorine atom and R ₃ is a hydrogen atom, a 2,8-diazobicyclo [4.3.0] non-8-yl radical, or a radical of structure wherein R ₄ , R ₅ and R ₆ are identical or different and represent hydrogen atoms or methyl radicals, or any of its pharmaceutically acceptable salts. Method according to claim 1, for the treatment or prevention of nephrotic syndromes, characterized in that a product belonging to the class of fluoroquinolones selected from pef loxacin, sparfloxacin, ciprofloxacin, ofloxacin, levofloxacin, enoxacin, norfloxacin is accepted , lomefloxacin, temafloxacin, amifloxacin, tozufloxacin, flumexin, rufloxacin, clinafloxacin, Wau-y-3118 or PD 131 628 or any of their pharmaceutically acceptable salts. A pharmaceutical composition for the preventive or therapeutic treatment of nephrotic syndromes, characterized in that it contains at least one product in the class of fluoroquinolones determined according to claim 1, in pure form or together with one or more diluents and / or compatible and pharmaceutically acceptable additives.