COMBINED USE OF N-IMIDAZOLYL DERIVATIVES OF BICYCLIC COMPOUNDS AND CYCLOSPORINE IN THERAPY

Abstract: The invention relates to the use of N-imidazolyl derivatives of bicyclic compounds of general formula (I), wherein (a) compound alpha is (II) wherein Y completes a single bond or is oxygen or a -CH2- group and the symbol --- represents a single or double bond or (b) compound alpha is (III) and the symbol --- represents a double bond; one of R1, R2, R3 and R4 is -CH2OH, C2-C4 acyl, (IV), -COOR7, -CH2COOR7, (V), (VI) or (VII) in which each of R7, R8 and R9 is independently hydrogen or C1-C4 alkyl, and the others are independently chosen from hydrogen, hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy and -COOR7 wherein R7 is as defined above; and one of R5 and R6 is hydrogen and the other is hydrogen, C1-C6 alkyl or phenyl; or a pharmaceutically acceptable salt thereof, in particular in combination with cyclosporin A. The compounds obtained are useful in preventing and/or treating cyclosporin A-induced nephrosis in mammals.

Description: COMBINED USE OF N-IMIDAZOLY DERIVATIVES OF BICYC IC COMPOUNDS AND CYCLOSPORINE IN THERAPY The present invention relates to the use of N-imidazolyl derivatives of bicyclic ccompounds, in particular in combination with cyclosporin A, in therapy. Cyclosporin A (CyA) is an effective immunosuppressive agent that dramatically improves allograft survival in human transplantation. At the same time, the use of cyclosporin A has been applied to various diseases thought to have auto¬ immune basis (including for example: multiple sclerosis, Guillan Barre syndrome, uveitis, myasthenia gravis, Heymann nephritis, juvenile diabetes type I, systemic lupus erythematosus, aplastic anaemia, pure red cell anaemia, idiopathic thrombocytopaenia, polychondritis, sclerodoma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, auto-immune male infertility, psoriasis and psoriatic arthiritis, Steven-Johnson syndrome, idiopathic sprue, Chrone's disease, sarcoidosis, glomerulonephritis, interstitial lung fibrosis and primary biliary cirrhosis) and to inflammatory conditions, in particular inflammatory conditions with an aetiology including an auto-immune component such as arthritis and rheumatic diseases. Reports and results _in vitro, in animal models and in clinical trials in the above-mentioned diseases are wide¬ spread in literature. However, the therapeutic potential of this drug is often limited by renal dysfunction characterized by a dose-dependent decrease in glomerular filtration rate (GFR) and creatinine clearance and increased blood urea nitrogen levels, as reported in Ann. Inter. Med. ££ 851 (1983)? Lancet 0., 470 (1981) and N. Engl. J. Med. 311, 699 (1984). The mechanism responsible for CyA-induced renal failure has not been fully elucidated. However, on the other hand, preservation of tubular function with the absence of frank tubular necrosis does not support a direct toxic effect of CyA on tubular cells. Therefore, the nephrotoxic effect of CyA may be more likely caused by altered hemodynamics, as it is associated with reduced renal blood flow and a progressive narrowing of the afferent arteriolar lumenal diameter, as shown by scanning electron microscopy. The basis for renal vasoconstriction is unclear, but it has been suggested that thromboxane (TxAA is a potential mediator of altered hemodynamics. TxA-, a cyclooxygenase metabolite of arachidonic acid, is a potent vasoconstrictor and platelet proaggregatory agent that has been implicated in many pathological processes. For instance increased renal xA 2 synthesis has recently been associated with the i munologically mediated renal injury characteristic of urine lupus. Cyclosporin A has been reported to alter arachidonic acid (A.A.) metabolism in some in vitro models of cultured monocytes and of smooth muscle cells [Lipids, 1£, 566 (1983) and Transplantation r 377 (1984)]. Moreover in vivo studies have shown that chronic administration of CyA in the rat induces a progressive increase in the renal synthesis of TxA 2 (Am. J. Physiol. 251, F 581-587 (1986)). Therefore, means of reducing this side effect would clearly be of major benefit. We have now found that cyclosporin A-induced nephrotoxicity can be limited by concomitant administration of a therapeutically effective amount of a N-imidazolyl derivative of formula (I) , as herein defined, or a pharmaceutically acceptable salt thereof. Accordingly in one aspect the present invention relates to a method of preventing or treating cyclosporin A-induced nephrotoxicity in mammals by administration of a therapeutically effective amount of a compound of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof. In another aspect the invention provides the use of a compound of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for use in preventing or treating cyclosporin A-induced nephrosis. The present invention further provides a method of treating a disease having an auto-immune basis, which method comprises concomitantly administering (1) a pharmaceutical composition containing a compound of formula (I) , as herein defined, or a pharmaceutically acceptable salt thereof, and (2) a pharmaceutical composition comprising cyclosporin A as active agent. The invention also provides products containing a compound of formula (I) or pharmaceutically acceptable salt thereof and cyclosporin A as a combined preparation for simultaneous or sequential use in treating a disease having an autoimmune basis. Ihe N-imidazolyl derivatives, accor ^ to the method of prevention or treatment provided by the present invention , are described in US-A-4 , 510 ,149 and in GB-B-2, 141 , 705 and have the following formula (I ) wherein (a) wherein Y completes a single bond or is oxygen or a -CH.- group and the sy repre¬ sents a single or a double bond or (b) Z is and the symbol represents a double bond; one of R , R , R and R is -CH.OH, p -C 4 acyl, / η / η -CON , -C00R ? , -CH 2 -C00R_, -CH.-CON , R B " R 8 in vhich each of R_7, RO β and R is independently hydrogen or C.-C alkyl,.and the others are independently chosen from hydrogen, hydroxy, halogen, C 1~ C alkyl, C -C 4 alkoxy and -C00R_ wherein R_ is as de¬ fined above; and one of R_ and R_ is hydrogen and the other is hydrogen, C -C 8 alkyl or phenyl. Preferred compounds of formula (I) are those wherein Z is one of R , R , and R 4 is -CH OH, C -C acyl, -CON , -C00R ? , -CH -C00R , -CH -CON R 8 XR 6 in which each of R , R and R Q is independently hydrogen or C -C alkyl, and the others are hydrogen andR_b and Ro_ are hydrogen; and the pharmaceu- tically acceptable salts thereof. Examples of preferred compounds of formula (I) are the fol- lowing: 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-carboxynap thaiene; 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-carboxynaphthalene; 2- (1-imidazolyl)-7-carboxynaphthalene; 2-(1-imidazolyl)-6-carboxynaphthalene; and the pharmaceutically acceptable salts thereof and, when appropriate, the C,-C. alkyl esters thereof. Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts, with inorganic, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric, acids, or organic, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, and salicyclic acids, and salts with inorganic, e.g. alkali metal, especially sodium or potassium, bases or alkaline-earth metal, especially calcium or magnesium, bases, or with organic bases, e.g. alkylamines, preferably triethylamine. A halogen atom is, for example, fluorine, chlorine or bromine, preferably chlorine or bromine. The alkyl and alkoxy groups may be branched or straight chain groups. A C.-Cg alkyl group may be a C,-C. alkyl group. Preferably the alkyl group is methyl or ethyl. A C,-C. alkoxy group is preferably methoxy or ethoxy. As stated above, the compounds of formula (I) , as well as the preferred ones hereabove specifically mentioned, are already described in US-A-4,510,149 and GB-B-2,141,705. The details of their preparation are described in the above- identified US and British patents. The compound of formula (I) or salt thereof and the cyclosporin A are typically formulated separately and presented for use in separate pharmaceutical compositions. The separate formulations may be administered simultaneously or sequentially. By "concomitant" and "combined" administration according to the present invention is therefore meant both separate and substantially contemporaneous administrations of cyclosporin A and of a compound of formula (I), as herein defined, or a phara ceutically acceptable salt thereof. The separate treatment with a compound of formula (I) , or a pharmaceutically acceptable salt thereof, can commence prior to cyclosporin A treatment or subsequent to the commencement of cyclosporin A treatment. A compound of formula (I) or one of its salts can therefore be administered 1 or 2 days in advance of commencing cyclosporin A treatment, so as to limit the nephrotoxic effects of cyclosporin A. Alternatively the treatment with the compound of formula (I) or salt thereof may begin at the same time as or at any time after commencement of cyclosporin A treatment, i.e. when the nephrotoxic effect of cyclosporin A is detected or when it is desired to prevent it. Doses of cyclosporin A to be administered in practising the invention will of course vary depending upon, e.g., the mode of administration, the condition to be treated (e.g. whether treatment is for the purposes of immunosuppression or otherwise, and if for immunosuppression whether for use in relation to e.g. organ transplant, bone marrow transplant, or the treatment of auto-immune disease) , as well as the effect desired. In addition, dosaging will generally require adjustment for individual patients in order to establish an appropriate long term drug serum concentration e.g. by administration of an initial daily starting or "loading" dose with subsequent dose adjustment (generally dose reduction) in accordance with serum levels, e.g. as determined by regular radioimmunoassay (RIA) monitoring. In general, amounts administered will be of the same order to those conventionally employed in cyclosporin A therapy, i.e. required to achieve (i) inmiunosuppressive or (ii) anti-inflammatory effectiveness. Thus, in general, satisfactory results are obtained on administration in a dose range of from about 5 or about 10 to about 20 mg/kg/day during the initial phase of therapy, reducing to a maintenance dose of from about 1 to about 5 to about 10 mg/kg/day administered to the patient orally, once or in divided doses 1 or 3 times a day. Where i.v. administration is required, e.g. administration by infusion (for example in the initial phase of treatment) lower dosages, e.g. of the order of from about 1 or about 3 to about 5 mg/kg/day for an initiating dose, or to about 2.5 mg/kg/day for a maintenance dose, are generally indicated. The toxicity of the compounds of formula (I) is negligible, therefore they can be safely used in therapy. • 3 - Mice .and rats which had been deprived of food for nine hours were treated orally with single administrations of increasing doses of compounds of the invention, then hous¬ ed and normally fed. The orientative acute toxiclty (LD_ Λ ) was assessed on the seventh day after the treatment and was higher than 800 mg/kg. In view of their high therapeutic index the compounds of formula (I) can be safely used in medicine. The dosage level suitable for oral administration to adult humans of the compounds of formula (I), e.g. 1,2-dihydro- 3-(1-imidazolyl)-6-carboxy-naphthalene, may range from about 100 mg to about 800 mg per dose 1 to 3 times a day, prefer¬ ably from about 200 mg to about 400 mg per dose 1 to 3 times a day. The exact dosage depends on the age, weight, condi- tion of the patient and administration route. Cyclosporin A and a compound of formula (I), or a pharma¬ ceutically acceptable salt thereof, can be administered in a variety of dosage forms, e.g., orally, in the form of tab¬ lets, capsules, sugar, or film coated tablets, liquid εolu- tions or suspensions; rectally, in the form of suppositories; parenterally, e.g. intramuscularly; or by intravenous injec¬ tion or infusion. The present invention also provides a kit comprising in se¬ parate containers (1) a pharmaceutical composition contain- ing an effective amount of a compound of formula (I), as - 1 <o - herein defined, or a pharmaceutically acceptable salt there¬ of, as active ingredient, and (2) a pharmaceutical composi¬ tion containing an effective amount of cyclosporin A r as active ingredient. The pharmaceutical compositions can be usually prepared fol¬ lowing conventional methods and administered in a pharmaceu¬ tically suitable form. For example, the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, sac- charose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, εtearic acid, magnesium or calcium εtea- rate, and/or polyethylene glycols; binding agentε, e.g. starches, arable gums, gelatin, methylcelluloεe, carboxy- methylcellulose or polyvinyl pyrrolidone; disaggregating agentε, e.g. a starch, alginic acid, alginates or εodiu εtarch glycolate; efferveεcing mixtures; dyestuffε; sweeten¬ ers; wetting agents, such as lecithin, polyεorbateε, lauryl- εulphateε; and, in general, non-toxic and pharmacologically inactive εubεtances uεed in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating processes. The liquid dispersions for oral administration may be e.g. syrups, emulsions, and suspensions. The syrup may contain as carrier, for example, saccharose or saccharoεe with gly- - ηη - cerine and/or mannitol and/or εorbitol. The suεpenεions and the emulεions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl al- cohol. The εuspensions or solutionε for intramuεcular injections may contain, together with the active compound, a pharmaceu¬ tically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g., propylene glycol, .and if de- sired, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions. The suppositories may contain together with the active com¬ pound a pharmaceutically acceptable carrier, e.g. cocoa-but¬ ter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. The following examples illustrate but do not limit the pre- sent invention. Example 1 The activity of a representative compound according to the present invention, i.e. l,2-dihydro-3-(1-imidazolyl)-6- carboxynaph halene, internal code FCE 2217B, was evaluated by the following method: Three groups of male Sprague-Dawley rats with initial weights of.250-275 g were used in this study. All animals were housed in a constant-temperature room with a 12-h light-dark cycle, fed standard rat chow (Altromin-Rieper, Vandoies, Italy) , and had free access to tap water. Group I received CyA (Sandoz, Basle, Switzerland) orally by gastric tube for 12 months at the dose of 40 mg/kg every other day. Thereafter the drug was discontinued and the animals were monitored for another 2 months without any treatment. Group 2 received for 12 months an oral dose of the vehicle, polyoxyethylenated castor oil (Sabo, Bergamo, Italy) , in which CyA (40 mg/kg) was dissolved and was considered as control group. Group 3 received an oral dose of CyA of 40 mg/kg every other day, the compound FCE 22178 at the daily dose of 50 mg/kg per os and a further amount of compound FCE 22178 at the dose of 100 mg/kg dissolved in drinking water both for 12 months. Compound FCE 22178 was administered concomitantly to CyA treatment, i.e. either just before or just after CyA treatment. Twenty-four-hour urine samples were collected at monthly intervals using metabolic cages and were immediately frozen and stored at -20'C until the extraction and the radio- immunoassay (RIA) for thromboxane (TX) B 2 , 6-keto- prostaglandin F lα (PGF lα ) , and prostaglandin (PG) E 2 , which reflects the renal synthesis of TXA , prostacyclin (PG1 ) , and PGE 2 , respectively, was performed. Blood samples for determination of serum TXB. concentration were collected from the tail vein at monthly intervals. In addition, every month five rats from each group underwent renal clearance studies. After the clearances, the kidneys were removed .and analyzed by light microscopy. Concomitant adminiεtration of compound FCE 22178 markedly inhibited TXA_ εyntheεis (measured as TXB levelε) in whole blood and reduced the εignificant increase of TXB- uri¬ nary excretion, creatinine and blood urea nitrogen: i.e. parameters that are indicative of abnormal renal function. Therefore the concomitant administration of compound FCE 22178 ameliorated the renal function. Example 2 Tablets, each weighing 300 mg and containing 100 mg of the active substance can be manufactured as follows: Compoεitions (for 10,000 tabletε) l,2-dihydro-3-(1-imidazolyl)-β-carboxynaphthalene 1000 g Lactoεe 1420 g Corn starch 475 g Talc powder 75 g Magnesium stearate 30 g 1,2-dihydro-3-(1-imidazolyl)-carboxy-naphthalene, lactose and a half of the corn starch are mixed; the mixture is then forced through a sieve of 0.5 mm openings. Corn starch (36 mg) is suspended in warm water (350 ml) . The resulting paste is used to granulate the powder. The granules are dried, comminuted on a sieve of sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium are added, carefully mixed, and processed into tablets using punches of 10 mm diameter. EXAMPLE 3: Intramuscular injection An injectable pharmaceutical composition can be manufactured by dissolving 100 mg of l,2-dihydro-3-(l- imidazolyl)-6-carboxynaphthalene sodium salt in sterile water or sterile normal saline solution (1-2 ml) . EXAMPLE 4; Capsules (100 mg) l,2-dihydro-3-(1-imidazolyl)-6-carboxynaphthalene 100 mg Lactose 248 mg Corn starch 50 mg Magnesium stearate 2 mg Total 400 mg Encapsulate in two-piece hard gelatine capsules. EXAMPLE 5: Suppository (100 mg) l,2-dihydro-3-(1-imidazolyl)-6-carboxynaphthalene 0.10 g Lecithin 0.14 g Cocoa butter 1.76 g Total 2.00 g

Claims: CLAIMS 1) The use of a compound of formula (I) wherein wherein Y completes a single bond or iε oxygen or a -CH 2 - group and the symbol represents a single or a double bond or (b) λZ is J J and the symbol representε a double bond; one of R lf R 2 , R 3 and R 4 iε -CH 2 0H, C -C 4 acyl, in which each of R 7 , R β and Ro is independently hydrogen or C^-C^ alkyl, and the others are independently chosen from hydrogen, hydroxy , halogen , C χ -C 4 alkyl , C χ -C 4 alkoxy .and -C00 wherein R_. iε aε de¬ fined above ; and one of R and R_ is hydrogen .and the other is hydrogen , C -C 8 alkyl or phenyl ; or a pharmaceutically acceptable salt thereof} in the preparation of a pharmaceutical compoεition for uεe in preventing or treating cycloεporin A-induoed nephrosis. ) The use according to claim 1 , wherein in formula (I) Z is one of R , R_ , R_ and R iε -CH OH , C_-C acyl , -CON , -C00R ? , -CH 2 -C00R ? , -CHg-CON R 8 XR 8 and R g iε independently hydrogen or C,-C 4 alkyl, .and the otherε are hydrogen. andRg and R g are hydrogen. ) The uεe according to claim 1 , whexein the said compound of formula (I) or salt thereof is selected from the group consisting of: 1,2-dihydro-3-(1-imidazolyl)-6-carboxynaphthalene; l,2-dihydro-3-(l-imidazolyl)-6-ethoxycarbonylnaphthalene; 1,2-dihydro-3-(1-imidazolyl)-6-hydroxymethylnaphthalene; 1,2-dihydro-3-(1-imidazolyl)-7-carboxynaphthalene; l,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-carboxynaphthalene; 2-(1-imidazolyl)-7-carboxynaphthalene; 2-(1-imidazolyl)-6-carboxynaphthalene; or the pharmaceutically acceptable salts thereof. 4) A method of treating a disease having an auto-immune basis, which comprises concomitantly administering (1) a pharmaceutical composition containing a compound of formula (I) s a single bond or is oxygen or a -CH 2 - group and the symbol represents a single or a double bond or (b) Z iε and the symbol z represents a double bond; one of Ri, R 2 , 3 and R 4 is -CH 2 OH, C 2 -C 4 acyl. -CON in which each of R 7 , R 8 and Rg is independently hydrogen or Cι«C 4 alkyl, and the others are independently chosen from hydrogen, hydroxy, halogen, Cι~C 4 alkyl, C;L-C 4 alkoxy and -COOR 7 wherein R 7 is as defined above; and one of R 5 and Rg iε hydrogen and' the other iε hydrogen, C -C alkyl or phenyl; or a pharmaceutically acceptable salt thereof; and (2) a pharmaceutical composition comprising cyclosporin A as active agent. A kit for use in treating a disease having an auto-immune basis, which kit comprises in separate containers (1) a pharmaceutical composition containing a compound of formula (I) wherein a) z is wherein Y completes a single bond or is oxygen or a -CH 2 - group and the symbol represents a single or double bond or (b) Z iε and the symbol represents a double bond; one of A , 2 , . and . is -CH-OH, C--C. acyl, R 7 R_ -CON , -COOR_, -CH--COOR 7 , -CH--CON , \ 2 7 2 χ R 8 R 8 in which each of R ? , R g and R g is independently hydrogen or C.-C. alkyl, and the others are independently chosen from hydrogen, hydroxy, halogen, C,-C. alkyl, C.-C. alkoxy and -COOR- wherein R_ is as defined above; and one of R- and β is hydrogen and the other is hydrogen, C.-C 8 alkyl or phenyl; or a pharmaceutically accpetable salt thereof; and (2) a pharmaceutical composition comprising cyclosporin A as active agent. 6. A method according to claim 4, wherein the said compound of formula (I) or εalt thereof iε aε defined in claim 2 or 3. 7. A kit according to claim 5, wherein the said compound of formula (I) or salt thereof iε as defined in claim 2 or 3. 8. Products containing a compound of formula (I) or pharmaceutically acceptable salt thereof as defined in claim 1 and cyclosporin A as a combined preparation for simultaneous or sequential use in treating a disease having an autoimmune basis. 9. Products according to claim 8, wherein the said compound of formula (I) or salt thereof is as defined in claim 2 or 3. 10. A method of preventing or treating cyclosporin A-induced nephrotoxicity in mammals, which method comprises administering to a mammal in need of it a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 3.

Inventors: ALESSANDRINI PAOLA, COZZI PAOLO, FERTI CORRADO, SALVATI PATRICIA, ALESSANDRINI, PAOLA, COZZI, PAOLO, FERTI, CORRADO, SALVATI, PATRICIA
Applicants: ERBA CARLO SPA, FARMITALIA CARLO ERBA S.R.L.
Application year: 1990
Main classification: A61K37
IPC codes: A61K38, A61P37, C07D233, C07D405