PT94464A - A process for the preparation of a pharmaceutical composition suitable for use in combination with N-IMIDAZOLYLIC DERIVATIVES OF BICYCLIC COMPOUNDS AND CYCLOSPORINE - Google Patents

Description

FARMITALIA CARLO ERBA S.R.L. " A process for the preparation of a pharmaceutical composition suitable for the combined use in therapy of N-imi dazolyl derivatives of bicyclic compounds and of cyclosporin " The present invention relates to a process for the preparation of a pharmaceutical composition containing N-imi-dazolyl derivatives of bicyclic compounds for use in therapy, in particular in combination with cyclosporin A. Cyclosporin A (CiA) constitutes an effective immunosuppressive agent that dramatically increases the survival of transplanted organs in humans. Concomitantly, cyclosporin A has been applied in the treatment of various diseases which are assumed to have an autoimmune (including for example: multiple sclerosis, Guillan Barre syndrome, uveitis, myasthenia gravis, Heymann's nephritis, juvenile type I diabetes, systemic lupus erythematosus, aplastic anemia, red blood cell anemia, idiopathic thrombocytopenia, polychondritis, sclerodoma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, autoimmune male infertility, psoriasis and psoriatic arthritis, Steven-Johnson syndrome, idiopathic psilosis, Chrone's disease, sarcoidosis, glomerulonephritis, interstitial lung fibrosis and primary biliary cirrhosis) and for inflammatory conditions, in particular inflammatory conditions with an etiology including an autoimmune component such as arthritis and rheumatic diseases .

There are reports and results on in vitro assays obtained with guinea pigs and in clinical trials on the previously mentioned diseases, which are widely reported

However, the therapeutic potential of this drug is often limited by renal dysfunction characterized by a dose-dependent decrease in the glomerular filtration rate (KFG) and by creatinine clearance and by the increase of the blood urea nitrogen levels, as described in " Ann. Inter. Med. 99: 851 (1983); Lancet 1, 470 (1981) and N. Engl. J. Med., 311, 699 (1984). The mechanism responsible for renal impairment induced by CiA has not yet been fully studied. However, on the other hand, preservation of tubular function with the absence of clear tubular necrosis does not favor the direct toxic effect of CyA on tubular cells. As a consequence, the nephrotoxic effect of CyA is most likely caused by altered hemodynamics, the action of which is associated with reduced renal blood flow and a progressive narrowing of the afferent artery lumenal diameter, as demonstrated by electron-scanning microscopy. The basis for renal vasoconstriction is not clear, but it has been suggested that thromboxane (TxA) is a potential intermediate agent of altered hemodynamics. 3e is a cyclooxygenase metabolite of arachidonic acid, it is a potent vasoconstrictor and a platelet pro-aggregating agent which is associated with many pathological processes. For example, increased renal TxA synthesis has recently been associated with indirectly-mediated renal damage characteristic of murine lupus. Cyclosporin A was associated with changes in arachidonic acid (A.A.) metabolism in some in vitro, monocyte culture and smooth muscle cells, Lipids, 18,

, 566 (1983) and Transplantation 38, 377 (1984) J. In addition, in vivo studies have shown that chronic administration of CyA in the rat induces the progressive increase of renal TxA2 synthesis (" Am. J. Physiol., 251, Ep. 1986 581-587). Consequently, the means to reduce this side effect are clearly of fundamental importance. The inventors have now discovered that cyclosporin A-induced nephrotoxicity may be limited by simultaneous administration in a therapeutically effective amount of an N-imidazolyl derivative of formula (I) as defined herein, or of. a pharmaceutically acceptable salt thereof. Accordingly, in accordance with one of its aspects, the present invention relates to a method of preventing or treating cyclosporin A-induced nephrotoxicity by mammalian administration. a therapeutically effective amount of a compound of formula (I) as defined herein, or an acceptable salt thereof. in pharmacy.

According to another aspect, the present invention provides the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for use in preventing or to treat nephrosis induced by cyclosporin A.

In addition, the present invention provides a method for the treatment of a disease having an autoimmune basis, said method comprising administering simultaneously (1) a pharmaceutical composition containing a compound of formula (I) as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and (2) a pharmaceutical composition incorporating cyclosporin A as an active ingredient. The present invention also provides products which have a compound of formula (I) or a pharmaceutically acceptable salt thereof and cyclosporin A, in the form of a combined preparation, for simultaneous or sequential use in the treatment of a disease which have an autoimmune base.

The N-imidazolyl derivatives according to the method of prevention or treatment provided by the present invention are described in U.S. Patent Applications Nos. A-4510149 and British No. -2141705 and have the following general formula

in which Y completes a single bond or represents an oxygen atom or a -CH 2 - group and the symbol has a single or double bond or (b) and Z represents and the symbol --- represents a bond double; or one of the radicals R 1, R 2, R 2, R 2, R 3, R 4,

<

-CON

-CH = C-COORg or -CH = C-CON, wherein each of R,, R e and R representa is independently hydrogen or C ^-C alquilo alkyl; are selected from halogen, hydroxy, C 1 -C 4 alkyl, C 2 -C 4 alkoxy, or 0,1 -C (O) R 3 in which R 7 has the meanings defined above; and one of R1 and R2 is a hydrogen atom and the other is hydrogen, C1 -C6 alkyl or phenyl.

Preferred compounds of general formula (I) are those in which the radical Z represents a group of formula

one of R1, R2, R3 and R4 is -CH2 OH, C2 -C4 acyl, or a group of the formula -CON, -COOR7, -CH2 -COOR7, - CH2-CONH-8

R = -CH = C-CO-R10 or -CH = C-CON8 wherein each of R7, R6

R6 and R6 are independently hydrogen, C1-C4 alkyl and the others represent a hydrogen atom, and R2 and R3 each independently represent a hydrogen atom ; and their pharmaceutically acceptable salts.

As examples of preferred compounds of formula (d) the following compounds are indicated: 1,2-dihydro-3- (1-imidazolyl) -6-carboxynnaphthalene; 1,2-dihydro-3- (1-imidazolyl) -6-ethoxycarbonylnaphthalene; 1,2-dihydro-3- (1-imidazolyl) -6-hydroxy-methyl-naphthalene; 1,2-dihydro-3- (1-imidazolyl) -7-carboxynnaphthalene; 1,2-dihydro-3- (1-imidazolyl) -6- (2-carboxy-vinyl) -naphthalene; 1,2-dihydro-3- (1-imidazolyl) -6- (2-ethoxycarbonyl-vinyl) -naphthalene; 1,2-dihydro-3- (1-imidazolyl) -6-carboxymethyl-naphthalene; 1,2,3,4-tetrahydro-2- (1-imidazolyl) -7-carboxynnaphthalene; 2- (1-imidazolyl) -7-carboxynnaphthalene; 2- (1-imidazolyl) -6-carboxynnaphthalene; and pharmaceutically acceptable salts thereof and, where appropriate, their C1-4 alkyl esters.

The pharmaceutically acceptable salts of the compounds of general formula (I) include acid addition salts, for example inorganic acids such as nitric, hydrochloric, hydrobromic, sulfuric, perchloric and phosphoric acids, or organic acids such as acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicyclic acids and also inorganic salts, for example of alkali metals, especially sodium or potassium, alkaline earth metal bases, in particular calcium or magnesium, or organic bases, for example alkyl amines, preferably triethylamine.

Suitable halogen atoms include, for example, fluorine, chlorine or bromine atoms, with the preference being the chlorine or bromine atom.

The alkyl and alkoxy groups may be straight chain or branched.

A C1 -C4 alkyl group may be a C1 -C4 alkyl group. Preferred alkyl groups are methyl or ethyl groups. Preferred C1-4 alkoxy groups are methoxy or ethoxy groups.

As mentioned above, the compounds of formula (I), as well as the preferred compounds specifically mentioned above, are already described in U.S. Patent Nos. 4,510,149 and British Patent No. 2141705. Details for their preparation are described in previously identified U.S. and UK patents.

The compounds of formula (I) or salts thereof and cyclosporin A are normally formulated separately and for use are presented in separate pharmaceutical compositions. The separate formulations may be administered simultaneously or sequentially. The terms " concomitant " and " combination " according to the present invention mean a separate and virtually contemporaneous administration of cyclosporin A and a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof from the point of view pharmaceutical. The separate treatment with a compound of formula (J) or a pharmaceutically acceptable salt thereof may commence prior to treatment with cyclosporin A or commence upon commencement of treatment with cyclosporin A.

Accordingly, a compound of formula (I) or a salt thereof may be administered one or two days prior to commencing cyclosporin A treatment, in order to limit the nephrotoxic effects of cyclosporin A. Alternatively, treatment with a compound of formula (I) or a salt thereof may commence at any time or at any time after initiation of cyclosporin A treatment, i.e., when the nephrotoxic effect of cyclosporin A is detected or whenever it is desired to avoid effect.

Doses of cyclosporin A that will be administered in accordance with the practice of the present invention will, of course, vary with the mode of administration, the condition to be treated (eg, treatment for immunosuppression or of another type, and in the case of immuno-suppression its use would depend, for example, on organ transplantation, bone marrow transplantation or treatment of an autoimmune disease), and also with the desired effect . In addition, dosage prescription will need to be adjusted to each patient in order to provide a long term serum drug concentration, for example, by administering a daily starting dose or a dose of " maintenance " with subsequent adjustment of that dose (usually a dose reduction) according to serum levels, for example as determined by regular control in radioimmunoassay (ERI) assays.

In general, the amounts administered will be of the same order of magnitude as those conventionally applied in cyclosporin A therapy, i.e., necessary to provide (i) an immunosuppressive or (ii) anti-inflammatory effect. Accordingly, satisfactory results are obtained by administering a dose of between 5 or 10 and 20 mg / kg / day during the initial phase of the therapy and then reducing it to a maintenance dose of between 1 and 5 and 10 mg / kg / day administered orally to a patient once or in divided doses 1 or 3 times per day.

If intravenous administration is required, for example infusion administration (for example at the initial stage of treatment), it is generally recommended to use doses in the range of from about 1 to 3 to about 5 mg / kg / day for the initial dose and less than 2.5 mg / kg / day for the maintenance dose. The toxicity of the compounds of formula (I) is negligible and can therefore be used in safe therapy.

Feeding mice and rats were used for 9 hours, which were orally treated with single administrations of increasing doses of compounds of the present invention, and then were caged and fed normally. The acute toxicity (DL, - q) was determined on the seventh day after treatment and found to be greater than 800 mg / kg.

In view of their high therapeutic index, the compounds of general formula (I) can be used in safe medicine.

Dosages suitable for oral administration to adult humans of compounds of general formula (I), for example 1,2-dihydro-3- (1-imidazolyl) -6-carboxynnaphthalene, may be comprised between about of 100 mg and about 800 mg per dose, 1 to 3 times per day, preferably between about 200 mg and about 400 mg per dose, 1 to 3 times per day. The exact dosage depends on the patient's age, weight, health status and route of administration. Cyclosporin A and a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered in a variety of dosage forms, for example orally, in the form of tablets, capsules, lozenges coated with sugar or a film, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, for example intramuscularly, or by intravenous injection or infusion. The present invention also provides a kit comprising separate containers containing (1) a pharmaceutical composition which contains an effective amount of a compound of formula (I) as defined herein, or an acceptable salt thereof, the pharmaceutical viewpoint as the active ingredient, and (2) a pharmaceutical composition which contains an effective amount of cyclosporin as an active ingredient.

The pharmaceutical compositions can usually be prepared using conventional methods and administered in a pharmaceutically suitable form.

For example, solid oral forms may contain, together with the active ingredient, diluents such as lactose, dextrose, sucrose, cellulose, cereal starch or potato starch; lubricants, such as silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; binding agents such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrole

lidone; disintegrating agents, such as starch, alginic acid, alginates or sodium starch glycolate; blending efferent mixtures; dyes; sweeteners; wetting agents, such as lecithin, polysorbates, lauryl sulfates; and, in general, the non-toxic and pharmacologically inactive substances used in the pharmaceutical formulations. Said pharmaceutical preparations may be prepared by a known process, for example, by mixing, granulating, pelleting, or by sugar coating processes.

Liquid dispersions for oral administration may be, for example, syrups, emulsions and suspensions. The powder may contain as carrier, for example, sucrose or sucrose with glycerol and / or mannitol and / or sorbitol.

The suspensions and emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

Suspensions or solutions for intramuscular injection may contain, together with the active ingredient, a pharmaceutically acceptable carrier, for example, sterile water, azeotriate, ethyl oleate, glycols, for example propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride.

Intravenous injection or infusion solutions may contain as carrier, for example, sterile water or, preferably, may be in the form of sterile, aqueous isotonic saline solutions.

The suppositories may contain, together with the active ingredient, a pharmaceutically acceptable carrier, for example, cocoa butter, polyethylene glycol, a polyoxy-12- ethylene sorbitan or lecithin.

The following examples illustrate but do not limit the present invention.

Example 1

The activity of a representative compound according to the present invention, i.e., the activity of 1,2-dihydro-3- (1-imidazole) -6-carboxynnaphthalene compound, the internal code i FCE 22178, as follows:

In this study three groups of male Sprague-Dawley strain with initial weight of 250-275 g were used. The animals were housed in a constant temperature compartment with a 12 hour light / dark cycle, fed standard rat food (Altromin-Rieper, Vandoies, Italy), and had free access to potable water. Group 1 received CiA (Sandoz, Basle, Switzerland) orally through a gastric tube for 12 months at a dose of 40 mg / kg each day. The drug was then discontinued and the animals were monitored for another two months without any treatment. Group 2 received, for 12 months, one oral vehicle, consisting of polyoxyethylated castor oil (Sabo, Bergamo, Italy), in which CiA (40 mg / kg) was dissolved and as a control group Group 3 received an oral dose of CiA of 40 mg / kg each day, compound FCE 22178 at the daily dose of 50 mg / kg orally and an additional amount of compound FCE 22178 at the dose of 100 mg / kg dissolved in the drinking water for 12 months in both cases Compound FCE 22178 was administered concomitantly with treatment with the CiA, i.e. immediately before or immediately after the treatment with CiA.

24-hour urine samples were collected at monthly intervals using metabolic cages and immediately frozen and stored at -20 ° C until extraction and radioimmunoassay (ERI) assay were performed for detection thromboxane (TX) B2, 6-keto-prostaglandin in F2 (PGE3), and prostaglandin (PG) E2, which respectively reflect the synthesis of TXA2 renai / prostacyclin (PG12), and PGE2 · Blood samples were collected at monthly intervals for the determination of serum TXB2 concentration. In addition, 5 rats from each group were submitted to renal observation studies every 5 months. After these studies the kidneys were removed and an optical microscope was analyzed. Concomitant administration of compound FCE 22178 clearly inhibited the synthesis of TXA2 (as measured by TXB2 levels) in blood and reduced the significant increase in urinary excretion of TXB2 from creatinine and blood urea nitrogen: i.e. the parameters constituting a abnormal renal function. As a consequence, it is concluded that concomitant administration of compound FCE 22178 improved renal function.

Example 2 It is possible to prepare tablets weighing each 300 mg and containing 100 mg of active ingredient, as follows:

Composition (for 10000 tablets) 1,2-dihydro-3- (1-imidazolyl) -6-carboxynnaphthalene 1000 g

Lactose 1420 g

Corn starch 475 g Talc powder 75 g -14-

Eur-lex.europa.eu eur-lex.europa.eu

Magnesium stearate 30 g

1,2-Dihydro-3- (1-imidazolyl) -carboxy-naphthalene, lactose and half of the corn starch were mixed; then the mixture was passed through a sieve with a 0.5 mm mesh. Corn starch (36 mg) was suspended in warm water (350 ml). The resulting slurry was used to granulate the powder. The granules were dried, sieved on a sieve having a mesh size of 1.4 mm and then the remaining amount of starch, talc and magnesium was carefully mixed and worked up to give pellets using 10 mm diameter drills.

Example 3: Intramuscular Injection An injectable pharmaceutical composition may be prepared by dissolving 100 mg of sodium salt of 1,2-dihydro-3- (1-imidazolyl) -6-carboxynnaphthalene in sterile water or in brine Normal sterilized paper (1-2 ml).

Example 4: Capsules (100 mg) 1,2-dihydro-3- (1-imidazolyl) -6-carboxynnaphthalene 100 mg

Lactose 248 mg

Corn starch 50 mg

Magnesium stearate 2 mg

Total 400 mg

The capsules are encapsulated into two part hard gelatin capsules.

Example 5: suppositories (100 mg) 0.10 g 0.14 g 1.76 g 1,2-dihydro-3- (1-imidazolyl) -6-carboxynnaphthalene Lecithin

Cocoa butter

Total 2.00 g

Claims (8)

A process for the preparation of a pharmaceutical composition suitable for use in the prevention or treatment of cyclosporin A induced nephrosis in mammals, characterized in that an effective amount comprised as active ingredient between 70 mg and 1400 mg of a compound of formula oxygen atom or a -CH 2 - group and the symbol - represents a single bond or a double bond or b) Z represents - and represents a double bond; R 2, R 2 and R 2 are -CH 2 OH or C 2 -C 4 acyl or a group of the general formula -NR 2 -CON, -CO 2 -C 2 -COOR 7, -CH 2 CON CON Wherein each of R7, R8 and R8 is independently hydrogen or C1 -C4 alkyl, and the compounds of formula (I) wherein R1, R2, R3 and R4 are independently hydrogen or C1-6 alkyl; others are independently selected from a hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and -CONR 7 in which R 7 is as defined above; and one of R1 and R2 is hydrogen and the other is a hydrogen atom or a C1 -C6 alkyl or phenyl group; 10 or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier and / or diluent. 2. A process according to claim 1, characterized in that a compound of formula (I) in which Z is a 17- R 1, R 2, R 3 and R 1 is or a group: Rr -CONR, -C00R7, -CH2 -COOR7, -CH2 -COOH R11 R7 Wherein each of R 1, R 2 and R 3 independently represents a hydrogen atom or a C 1 -C 4 alkyl group and the others represent a C 1 -C 4 alkyl group; hydrogen; and L and are a hydrogen atom. 3. A process according to claim 1, wherein a compound of formula (I) or a salt thereof selected from the group consisting of: 1,2-dihydro-3- (1-imidazolyl) 6-carboxynaphthalene; 1,2-dihydro-3- (1-imidazolyl) -6-ethoxycarbonylnaphthalene; 1,2-dihydro-3- (1-imidazolyl) -6-hydroxymethylnaphthalene; 1,2-dihydro-3- (1-imidazolyl) -7-carboxynnaphthalene; 1,2-dihydro-3- (1-imidazolyl) -6- (2-carboxyvinyl) naphthalene; 1,2-dihydro-3- (1-imidazolyl) -6- (2-ethoxycarbonylvinyl) -naphthalene; 1,2-dihydro-3- (1-imidazolyl) -6-carboxymethylnaphthalene; 1,2,3,4-tetrahydro-2- (1-imidazolyl) -7-carboxynnaphthalene; 2- (1-imidazolyl) -7-carboxynnaphthalene; 2- (1-imidazolyl) -6-carboxynnaphthalene; or pharmaceutically acceptable salts thereof. 4. A method for the treatment of a disease having an autoimmune base, characterized in that a pharmaceutical composition prepared by the process according to claim 1 is concomitantly administered to a patient; and 2) a pharmaceutical composition containing cyclosporin A as the active agent at doses ranging from about 5 to about 10 to about 20 mg / kg / day during the initial phase of therapy. 5. A kit for use in the treatment of a disease having an autoimmune base, characterized in that it comprises two separate containers, the first of which (1) contains a pharmaceutical composition prepared by the process according to claim 1, and the second (2) contains a pharmaceutical composition which includes cyclosporin A as the active agent. 6. A method according to claim 4, characterized in that a pharmaceutical composition prepared by the process according to claim 2 or 3 is used. 7.-. The kit according to claim 5, characterized in that a pharmaceutical composition prepared by the process according to claim 2 or 3 is used. 8. A method for preventing or treating mammalian nephrotoxicity induced by cyclosporin A, wherein administering to the mammal in need of such treatment an effective amount of from about 100 mg to about 800 mg per dose tone three times a day of a compound of general formula I or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 3. J, June 22, 1990, hereinafter Prophylactic )