CA2035032A1 - Combined use of n-imidazolyl derivatives of bicyclic compounds and cyclosporine in therapy - Google Patents
Combined use of n-imidazolyl derivatives of bicyclic compounds and cyclosporine in therapyInfo
- Publication number
- CA2035032A1 CA2035032A1 CA002035032A CA2035032A CA2035032A1 CA 2035032 A1 CA2035032 A1 CA 2035032A1 CA 002035032 A CA002035032 A CA 002035032A CA 2035032 A CA2035032 A CA 2035032A CA 2035032 A1 CA2035032 A1 CA 2035032A1
- Authority
- CA
- Canada
- Prior art keywords
- hydrogen
- coor7
- imidazolyl
- alkyl
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Abstract
ABSTRACT
COMBINED USE OF N-IMIDAZOLYL DERIVATIVES OF BICYCLIC
COMPOUNDS AND CYCLOSPORIN IN THERAPY
The invention relates to the use of N-imidazolyl derivatives of bicyclic compounds of general formula (I) wherein a) wherein Y completes a single bond or is oxygen or a -CH2- group and the symbol represents a single or double bond or (b) is and the symbol --- represents a double bond;
one of R1, R2, R3 and R4 is -CH2OH, C2-C4 acyl, , -COOR7, -CHCOOR7, , or
COMBINED USE OF N-IMIDAZOLYL DERIVATIVES OF BICYCLIC
COMPOUNDS AND CYCLOSPORIN IN THERAPY
The invention relates to the use of N-imidazolyl derivatives of bicyclic compounds of general formula (I) wherein a) wherein Y completes a single bond or is oxygen or a -CH2- group and the symbol represents a single or double bond or (b) is and the symbol --- represents a double bond;
one of R1, R2, R3 and R4 is -CH2OH, C2-C4 acyl, , -COOR7, -CHCOOR7, , or
Description
~ ~3 ~
. FC 445 COMBINED USE OF N-IMIDAZOLYL DERIVATIVES OF BICYCLIC
COMPOUNDS AN~ CYCLOSPORINE IN T~ERAPY
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 ~yclosporin A
has been applied to various diseases thought to have auto-immune basis (including for example: multiple sclerosis, Guillan Barre syndrome, uveitis, myasthenia gravis, ~eymann nephritis, juvenile diabetes type I, systemic lupus erythematosus, aplastic anaemia, pure red cell anaemia, idiopathic thrombocytopaenia, polychondritis, 6clerodoma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, auto-immune male infertility, psoriasis and psoriatic arthiritis, Steven-Johnson syndrome, idiopathic sprue, Chrone's disease, s~rcoidosis, glomerulonephritis, interstit$al lung fibrosis and primary bil~ary cirrhosis) and to inflammatory conditions, ln particulag inflammatory conditions with an aetiology lncluding an auto-immune component such as arthritis and rheumatic diseases.
Report~ and results in vitro, in animal models and in clinical trials in the above-mentioned diseases are wide-spread in literature. ~owever, the therapeutic potential of 20.'-3~1132 this drug is often limited by renal dysfunction characterized by a dose-dependent decrease in glomerular filtration rate (GFR) and creatinine clearance and increased blood urea nitrogen levels, as reported in Ann. Inter. Med.
99, 851 (1983); Lance~ 1, 470 ~1981) and N. Engl. J. Med.
311, 699 (1984).
The mechanism responsible for CyA-induced renal failure has not been fully elucidated. ~owever, on the other hand, preservation of tubular function with the absence of frank tubular necrosis does not support a direct toxic effect of CyA on tubular cells. Therefore, the nephrotoxic effect of CyA may be more likely caused by altered hemodynamics, as it is associated with reduced renal blood flow and a progressive narrowing of the afferent arteriolar lumenal diameter, as shown by scanning electron microscopy. The basis for renal vasoconstriction is unclear, but it has been suggested that thromboxane (TxA2) is a potential mediator of altered hemodynamics.
TxA2, a cyclooxygenase metabolite of ~rachidonic acid, is a potent vasoconstrictor and platelet proaggregatory agent that has been implicated in many pathological processes. For instance increased renal TXA2 synthe is has recently been associated with the immunologically mediated renal injury characteristic of murine lupus.
Cyclosporin A has been reported to alter arachidonic ~.3~3~
acid (A.~.) metabolism in some in v$tro models of cultured monocytes and of smooth muscle cells [Lipids, 18, 566 ~1983) and Transplantation 38, 377 (1984)~. Moreover in vivo studies have shown that chronic administration of CyA ln the rat induces a progressive $ncrease in the renal synthesis of TxA2 ~Am. J. Physiol. 251, F 581-587 (19B6)). Therefore, means of reducing this side effect would clearly be of major benefit.
We have now found that cyclosporin A-induced nephrotoxicity can be limited by concomitant administration of a therapeutically effective amount of a N-imidazolyl derivative of formula (I), 8S herein defined, or a pharmaceutically acceptable salt thereof. Accordingly in one aspect the present invention relates to a method of preventing or treating cyclosporin A-induced nephrotoxicity in mammals by administration of a therapeutically effective amount of a compound of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof.
In another aspect the invention provides the use of a compound of formula lI), as herein defined, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for use in preventing or treating cyclosporin A-induced nephrosis.
The present invention further provides a method of treating a disease having an auto-immune basis, which method comprifies concomitantly admin$stering ~1) a pharmaceutical composition containing a compound of formula (I), as ~erein defined, or a pharmaceutically acceptable salt thereof, and (2) a pharmaceutical composit$on comprising cyclosporin A as active agent.
The invention also provides products containing a compound of formula (I) or pharmaceutically acceptable salt thereof and cyclosporin A as a combined preparation for simultaneous or sequential use in treating a disease having an autoimmune basis.
S 0 ~ 2 The N- ~ dazolyl der~vatives, accon~ng to the nethod of prevention or treatment pro~ded by the present inventlon, are described ln US-A-4,510,149 and ~n GB-B-2,141,705 and have the following formula (I) ~ (I) wherein (a) JZ is ~ ~ wherein Y completes a single bond or is oxygen or a -CH2- group and thj symbol --- repre-sents a single or a double bond or tb) Z ls and the symbol --- represents a double ~ond;
one of Rl, R2, R3 and R4 is CH20H, C2-C4 acyl, / 7 ~ R7 -CON \ , -COOR7, -CH2-COOR7, -CH2-CON \
R17 C9 ~ 7 -CH=C-COOR8 or -CH= -CON ln which e~ch of R7, R8 and Rg ls independently hydrogen or Cl-C4 ~lkyl~and the others ~ ~, .3 ~ 3 ~
are independently chosen from hydrogen, hydroxy, halogen, Cl-C4 alkyl, Cl-C4 alkoxy and -COOR7 whereln R7 i8 as de-flned above; and one Or R5 and R6 ls hydrogen and the other is hydrogen, Cl-C6 alkyl or phenyl.
Preferred compounds of formula (I) are those whereln Z is or one of Rl, R2~ R3 and R4 is -CH20H, C2-C4 acyl, -CON , -COOR7, -CH2-COOR7, -~2-CON
-CH=C-COOR8 or -CH=C-CON ln which each of R7, R8 and RR
Rg is independently hydrogen or Cl-C4 alkyl,and the others are hydrogen andR5 and R6 are hydrogen; and the pharmaceu-tically acceptable salts thereof.
Examples of preferred compounds of formula (I) are the fol-lowing:
1,2-dihydro-3-(1-imidazolyl)-6-carboxynaphthalene;
1,2-dlhydro-3-(1-lmldazolyl)-6-ethoxycarbonylnaphthalene;
1,2-dihydro-3~ imldazolyl)-6-hydroxymethylnaphthalene;
1,2-dihydro-3-(1-imldazolyl)-7-carboxynaphthalene;
1,2-dihydro-3-(1-lmidazolyl)-6-(2-carboxyvlnyl)-naphthalene;
1,2-dihydro-3-~1-imldszolyl)-6-(2-ethoxycarbonylvinyl)-naphthalene;
1,2-dihydro-3-(1-imidazolyl)-6-carboxymethylnaphthalene;
1,2,3,4-tetrahydro-2-(1-$midazolyl)-7-carboxynaphthalene;
2-(1-imidazolyl)-7-carboxynaphthalene:
2~ imidazolyl)-6-carboxynaphthalene;
and the pharmaceutically acceptable salts thereof and, when appropriate, the Cl-C4 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 Cl-C6 alkyl group may be a Cl-C4 alkyl group.
Preferably ~he alkyl group is methyl or ethyl. A Cl-C4 alkoxy group is preferably methoxy or ethoxy.
As stated above, the compounds of formula (I), as ~03~032 well as the preferred ones hereabove specif~cally mentioned, are already described in US-A-4,510,149 and G2-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.
~he separate formulations may be administered simultaneously or sequentially. By ~concomitant~ and ~combined~
administratior. 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 pharamceutically 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, cO as to limit the nephrotoxic effects of cyclosporin A. Alternati~ely 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 admingstered in practisinq 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, ~nd if for immunosuppression whether for use in relation to e.g. organ transplant, bone n .~ ~
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) immunosuppressive 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 lO
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 l 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.
.
~ o~
Mice and rats which had been deprlved of food for nlne hours were treated orally with slngle admlnlstratiOns of increaslng doses of compounds of the lnventlon, then hous-ed and normally fed. ~he orlentative acute toxlclty (LD50) was assessed on the seventh day after the treatment and was higher than 800 mg/kg.
In view of their high therapeutlc lndex the compounds of formula (I) can be safely used in medicine.
The dosage level ~uitable for oral administratlon to adult humans of the compounds of formula (I), e.g. 1,2-dlhydro-3-(1-imidazolyl)-6-carboxy-naphthalene, may range ~rom 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 patlent 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 ~orm of tab-lets, capsules, sugar, or film coatcd tablets, llquld solu-tlons or suspensions; rectally, ln the form of suppositories;parenterally, e.g. intramuscularly; or by lntravenous lnJec-tlon or lnfuslon.
The present inventlon also provides a klt comprlsing in se-parate containers (1) a pharmaceutlcal composltlon contain-ing an ef~ective amount of a compGund of ~ormula (I), as f3 3 ~
10 .
herein defined, or a pharmaceutlcally accept~ble salt the~o~, as actlve ingredient, and t2) a pharmaceutlcal composl-tion containing an effectlve amount of cyclosporln A,as active ingredlent.
The pharmaceutical compositlons ean be usually prepared fol-lowing conventional methods and administered ln a pharmaceu-tically suitable form.
For example, the solid oral forms may contain, together wlth the active compound, diluents, e.g. lactose, dextrose, sac- -charose~ cellulose, corn starch or potato starch; lubricants,e.g. silica, talc, stearic acid, magnesium or calcium stea-rate, and/or polyethylene glycols; binding agents, e.g.
starches, arabic gums, gelatin, methylcellulose, carboxy-methylcellulose or polyvinyl pyrrolidone; dlsaggregating agents, e.g. a starch, a~ginlc acid, hlglnates or sodium starch glycolate; effervescing mlxtures; dyestuffs; sweeten-ers; wetting agents~ such as leclthin, polysorbates, lauryl-sulphates; and, in general, non-toxic and pharmacologlcally lnactive substances used ln pharmaceutical formulations.
Sald pharmaceutical preparatlons may be manufactured ln known manner, for example, by means of mixing, ~ranuiating, tablettlng, sugar-coatlng processes.
The llquld disperslons for oral admlnistration may be e.g.
~yrups, emulsions, and suspensions. The syrup may contain as carrier, for example, saccharose or saccharose wlth gly-~ ~ 3 ~ 2 cerlne and/or mannitol and/or sorbltol.The suspenslons and the emulsions may contaln as carrler, for example, a natural gum, agar, sodlum alglnate, pectln, methylcellulose, carboxymethylcellulose, or polyvlnyl al-5 cohol.
The suspensions or solutlons for lntramuscular lnJections 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 lf de-sired, a suitable amount of lidocaine hydrochlorlde.The solu~ions for intravenous inJectlons or infusions may contain as carriçr, for example, sterile water or preferably they may be in the form of sterile, aqueous, lsotonic sallne solutions.
The suppositories may contain together with ~he actlve com-pound a pharmaceutically acceptable carrier, e.g. cocoa-but-ter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithln.
The following examples illustrate but do not limlt the pre-sent invention.
;Example_l The activlty of a representatlve compound accordlng to the present lnventlon, i.e. 1,2-dlhydro-3-(1-lmldazolyl~-6-carboxynaphthalene, internal code FCE 22178, was evaluated by the following method:
~ ~ .
~ ~ ,n.~2 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) B2, 6-k~to-prostaglandin Fl~ (PGFl~), and prostaglandin (PG) E2, which reflects the renal synthesis of TXA2, prostacyclin (PG12), - and PGE2, respectively, was performed. Blood samples for determination 2~ rjn32 of 8erum TXB2 concentr~tlon were collected rro~ the tall veln at monthly lntervals. In addltlon, every month ~lve rats from each group underwent renal clearance studles.
Arter the clearances, the kldneys were removed and anslyzed by llght mlcroscopy.
Concomitant administration of compound FCE 22178 markedly inhibited TXA2 synthesis (measured as TX~2 levels) ln whole blood and reduced the signli~icant lncrease of TXB2 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 i~unction.
Example 2 Tablets, each weighing 300 mB and containing 100 mg of the active substance can be manufactured as follows:
Com~ositions (for 10,000 tablets) 1,2-dihydro-3~ imidazolyl)-6-carboxynaphthalene 1000 g Lactose 1420 g Corn starch 475 g Talc powder 75 g Magnesium stearate 30 g 1,2-dihydro-3~ imidazolyl)-carboxy-naphthalene, lactose 203~ 0~
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 i8 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 lO mm diameter.
EXAMPLE 3: Intramuscular in;ection An injectable pharmaceutical composition can be manufactured by dissolving 100 mg of 1,2-dihydro-3-(1-imidazolyl)-6-carboxynaphthalene sodium salt in sterile water or sterile normal saline solution (1-2 ml).
EXAMPLE 4: Capsules ~100 mg) 15 1,2-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) 1,2-dihydro-3-(1-imidazolyl)-6-carboxynaphthalene 0.10 g Lecithin 0.14 g - 25 Cocoa butter 1.76 g Total 2.00 g
. FC 445 COMBINED USE OF N-IMIDAZOLYL DERIVATIVES OF BICYCLIC
COMPOUNDS AN~ CYCLOSPORINE IN T~ERAPY
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 ~yclosporin A
has been applied to various diseases thought to have auto-immune basis (including for example: multiple sclerosis, Guillan Barre syndrome, uveitis, myasthenia gravis, ~eymann nephritis, juvenile diabetes type I, systemic lupus erythematosus, aplastic anaemia, pure red cell anaemia, idiopathic thrombocytopaenia, polychondritis, 6clerodoma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, auto-immune male infertility, psoriasis and psoriatic arthiritis, Steven-Johnson syndrome, idiopathic sprue, Chrone's disease, s~rcoidosis, glomerulonephritis, interstit$al lung fibrosis and primary bil~ary cirrhosis) and to inflammatory conditions, ln particulag inflammatory conditions with an aetiology lncluding an auto-immune component such as arthritis and rheumatic diseases.
Report~ and results in vitro, in animal models and in clinical trials in the above-mentioned diseases are wide-spread in literature. ~owever, the therapeutic potential of 20.'-3~1132 this drug is often limited by renal dysfunction characterized by a dose-dependent decrease in glomerular filtration rate (GFR) and creatinine clearance and increased blood urea nitrogen levels, as reported in Ann. Inter. Med.
99, 851 (1983); Lance~ 1, 470 ~1981) and N. Engl. J. Med.
311, 699 (1984).
The mechanism responsible for CyA-induced renal failure has not been fully elucidated. ~owever, on the other hand, preservation of tubular function with the absence of frank tubular necrosis does not support a direct toxic effect of CyA on tubular cells. Therefore, the nephrotoxic effect of CyA may be more likely caused by altered hemodynamics, as it is associated with reduced renal blood flow and a progressive narrowing of the afferent arteriolar lumenal diameter, as shown by scanning electron microscopy. The basis for renal vasoconstriction is unclear, but it has been suggested that thromboxane (TxA2) is a potential mediator of altered hemodynamics.
TxA2, a cyclooxygenase metabolite of ~rachidonic acid, is a potent vasoconstrictor and platelet proaggregatory agent that has been implicated in many pathological processes. For instance increased renal TXA2 synthe is has recently been associated with the immunologically mediated renal injury characteristic of murine lupus.
Cyclosporin A has been reported to alter arachidonic ~.3~3~
acid (A.~.) metabolism in some in v$tro models of cultured monocytes and of smooth muscle cells [Lipids, 18, 566 ~1983) and Transplantation 38, 377 (1984)~. Moreover in vivo studies have shown that chronic administration of CyA ln the rat induces a progressive $ncrease in the renal synthesis of TxA2 ~Am. J. Physiol. 251, F 581-587 (19B6)). Therefore, means of reducing this side effect would clearly be of major benefit.
We have now found that cyclosporin A-induced nephrotoxicity can be limited by concomitant administration of a therapeutically effective amount of a N-imidazolyl derivative of formula (I), 8S herein defined, or a pharmaceutically acceptable salt thereof. Accordingly in one aspect the present invention relates to a method of preventing or treating cyclosporin A-induced nephrotoxicity in mammals by administration of a therapeutically effective amount of a compound of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof.
In another aspect the invention provides the use of a compound of formula lI), as herein defined, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for use in preventing or treating cyclosporin A-induced nephrosis.
The present invention further provides a method of treating a disease having an auto-immune basis, which method comprifies concomitantly admin$stering ~1) a pharmaceutical composition containing a compound of formula (I), as ~erein defined, or a pharmaceutically acceptable salt thereof, and (2) a pharmaceutical composit$on comprising cyclosporin A as active agent.
The invention also provides products containing a compound of formula (I) or pharmaceutically acceptable salt thereof and cyclosporin A as a combined preparation for simultaneous or sequential use in treating a disease having an autoimmune basis.
S 0 ~ 2 The N- ~ dazolyl der~vatives, accon~ng to the nethod of prevention or treatment pro~ded by the present inventlon, are described ln US-A-4,510,149 and ~n GB-B-2,141,705 and have the following formula (I) ~ (I) wherein (a) JZ is ~ ~ wherein Y completes a single bond or is oxygen or a -CH2- group and thj symbol --- repre-sents a single or a double bond or tb) Z ls and the symbol --- represents a double ~ond;
one of Rl, R2, R3 and R4 is CH20H, C2-C4 acyl, / 7 ~ R7 -CON \ , -COOR7, -CH2-COOR7, -CH2-CON \
R17 C9 ~ 7 -CH=C-COOR8 or -CH= -CON ln which e~ch of R7, R8 and Rg ls independently hydrogen or Cl-C4 ~lkyl~and the others ~ ~, .3 ~ 3 ~
are independently chosen from hydrogen, hydroxy, halogen, Cl-C4 alkyl, Cl-C4 alkoxy and -COOR7 whereln R7 i8 as de-flned above; and one Or R5 and R6 ls hydrogen and the other is hydrogen, Cl-C6 alkyl or phenyl.
Preferred compounds of formula (I) are those whereln Z is or one of Rl, R2~ R3 and R4 is -CH20H, C2-C4 acyl, -CON , -COOR7, -CH2-COOR7, -~2-CON
-CH=C-COOR8 or -CH=C-CON ln which each of R7, R8 and RR
Rg is independently hydrogen or Cl-C4 alkyl,and the others are hydrogen andR5 and R6 are hydrogen; and the pharmaceu-tically acceptable salts thereof.
Examples of preferred compounds of formula (I) are the fol-lowing:
1,2-dihydro-3-(1-imidazolyl)-6-carboxynaphthalene;
1,2-dlhydro-3-(1-lmldazolyl)-6-ethoxycarbonylnaphthalene;
1,2-dihydro-3~ imldazolyl)-6-hydroxymethylnaphthalene;
1,2-dihydro-3-(1-imldazolyl)-7-carboxynaphthalene;
1,2-dihydro-3-(1-lmidazolyl)-6-(2-carboxyvlnyl)-naphthalene;
1,2-dihydro-3-~1-imldszolyl)-6-(2-ethoxycarbonylvinyl)-naphthalene;
1,2-dihydro-3-(1-imidazolyl)-6-carboxymethylnaphthalene;
1,2,3,4-tetrahydro-2-(1-$midazolyl)-7-carboxynaphthalene;
2-(1-imidazolyl)-7-carboxynaphthalene:
2~ imidazolyl)-6-carboxynaphthalene;
and the pharmaceutically acceptable salts thereof and, when appropriate, the Cl-C4 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 Cl-C6 alkyl group may be a Cl-C4 alkyl group.
Preferably ~he alkyl group is methyl or ethyl. A Cl-C4 alkoxy group is preferably methoxy or ethoxy.
As stated above, the compounds of formula (I), as ~03~032 well as the preferred ones hereabove specif~cally mentioned, are already described in US-A-4,510,149 and G2-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.
~he separate formulations may be administered simultaneously or sequentially. By ~concomitant~ and ~combined~
administratior. 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 pharamceutically 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, cO as to limit the nephrotoxic effects of cyclosporin A. Alternati~ely 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 admingstered in practisinq 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, ~nd if for immunosuppression whether for use in relation to e.g. organ transplant, bone n .~ ~
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) immunosuppressive 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 lO
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 l 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.
.
~ o~
Mice and rats which had been deprlved of food for nlne hours were treated orally with slngle admlnlstratiOns of increaslng doses of compounds of the lnventlon, then hous-ed and normally fed. ~he orlentative acute toxlclty (LD50) was assessed on the seventh day after the treatment and was higher than 800 mg/kg.
In view of their high therapeutlc lndex the compounds of formula (I) can be safely used in medicine.
The dosage level ~uitable for oral administratlon to adult humans of the compounds of formula (I), e.g. 1,2-dlhydro-3-(1-imidazolyl)-6-carboxy-naphthalene, may range ~rom 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 patlent 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 ~orm of tab-lets, capsules, sugar, or film coatcd tablets, llquld solu-tlons or suspensions; rectally, ln the form of suppositories;parenterally, e.g. intramuscularly; or by lntravenous lnJec-tlon or lnfuslon.
The present inventlon also provides a klt comprlsing in se-parate containers (1) a pharmaceutlcal composltlon contain-ing an ef~ective amount of a compGund of ~ormula (I), as f3 3 ~
10 .
herein defined, or a pharmaceutlcally accept~ble salt the~o~, as actlve ingredient, and t2) a pharmaceutlcal composl-tion containing an effectlve amount of cyclosporln A,as active ingredlent.
The pharmaceutical compositlons ean be usually prepared fol-lowing conventional methods and administered ln a pharmaceu-tically suitable form.
For example, the solid oral forms may contain, together wlth the active compound, diluents, e.g. lactose, dextrose, sac- -charose~ cellulose, corn starch or potato starch; lubricants,e.g. silica, talc, stearic acid, magnesium or calcium stea-rate, and/or polyethylene glycols; binding agents, e.g.
starches, arabic gums, gelatin, methylcellulose, carboxy-methylcellulose or polyvinyl pyrrolidone; dlsaggregating agents, e.g. a starch, a~ginlc acid, hlglnates or sodium starch glycolate; effervescing mlxtures; dyestuffs; sweeten-ers; wetting agents~ such as leclthin, polysorbates, lauryl-sulphates; and, in general, non-toxic and pharmacologlcally lnactive substances used ln pharmaceutical formulations.
Sald pharmaceutical preparatlons may be manufactured ln known manner, for example, by means of mixing, ~ranuiating, tablettlng, sugar-coatlng processes.
The llquld disperslons for oral admlnistration may be e.g.
~yrups, emulsions, and suspensions. The syrup may contain as carrier, for example, saccharose or saccharose wlth gly-~ ~ 3 ~ 2 cerlne and/or mannitol and/or sorbltol.The suspenslons and the emulsions may contaln as carrler, for example, a natural gum, agar, sodlum alglnate, pectln, methylcellulose, carboxymethylcellulose, or polyvlnyl al-5 cohol.
The suspensions or solutlons for lntramuscular lnJections 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 lf de-sired, a suitable amount of lidocaine hydrochlorlde.The solu~ions for intravenous inJectlons or infusions may contain as carriçr, for example, sterile water or preferably they may be in the form of sterile, aqueous, lsotonic sallne solutions.
The suppositories may contain together with ~he actlve com-pound a pharmaceutically acceptable carrier, e.g. cocoa-but-ter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithln.
The following examples illustrate but do not limlt the pre-sent invention.
;Example_l The activlty of a representatlve compound accordlng to the present lnventlon, i.e. 1,2-dlhydro-3-(1-lmldazolyl~-6-carboxynaphthalene, internal code FCE 22178, was evaluated by the following method:
~ ~ .
~ ~ ,n.~2 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) B2, 6-k~to-prostaglandin Fl~ (PGFl~), and prostaglandin (PG) E2, which reflects the renal synthesis of TXA2, prostacyclin (PG12), - and PGE2, respectively, was performed. Blood samples for determination 2~ rjn32 of 8erum TXB2 concentr~tlon were collected rro~ the tall veln at monthly lntervals. In addltlon, every month ~lve rats from each group underwent renal clearance studles.
Arter the clearances, the kldneys were removed and anslyzed by llght mlcroscopy.
Concomitant administration of compound FCE 22178 markedly inhibited TXA2 synthesis (measured as TX~2 levels) ln whole blood and reduced the signli~icant lncrease of TXB2 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 i~unction.
Example 2 Tablets, each weighing 300 mB and containing 100 mg of the active substance can be manufactured as follows:
Com~ositions (for 10,000 tablets) 1,2-dihydro-3~ imidazolyl)-6-carboxynaphthalene 1000 g Lactose 1420 g Corn starch 475 g Talc powder 75 g Magnesium stearate 30 g 1,2-dihydro-3~ imidazolyl)-carboxy-naphthalene, lactose 203~ 0~
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 i8 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 lO mm diameter.
EXAMPLE 3: Intramuscular in;ection An injectable pharmaceutical composition can be manufactured by dissolving 100 mg of 1,2-dihydro-3-(1-imidazolyl)-6-carboxynaphthalene sodium salt in sterile water or sterile normal saline solution (1-2 ml).
EXAMPLE 4: Capsules ~100 mg) 15 1,2-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) 1,2-dihydro-3-(1-imidazolyl)-6-carboxynaphthalene 0.10 g Lecithin 0.14 g - 25 Cocoa butter 1.76 g Total 2.00 g
Claims (10)
1) The use of a compound of formula (I) (I) wherein (a) wherein Y completes a single bond or is oxygen or a -CH2- group and the symbol represents a single or a double bond or (b) is and the symbol --- represents a double bond;
one of R1, R2, R3 and R4 is -CH2OH, C2-C4 acyl, ,-COOR7, -CH2-COOR7, , or in which each of R7, R8 and R9 is independently hydrogen or C1-C4 alkyl, and the others 16.
are independently chosen from hydrogen, hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy and -COOR7 wherein R7 is as de-fined 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 the preparation of a pharmaceutical composition for use in preventing or treating cyclosporin A-induced nephrosis.
one of R1, R2, R3 and R4 is -CH2OH, C2-C4 acyl, ,-COOR7, -CH2-COOR7, , or in which each of R7, R8 and R9 is independently hydrogen or C1-C4 alkyl, and the others 16.
are independently chosen from hydrogen, hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy and -COOR7 wherein R7 is as de-fined 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 the preparation of a pharmaceutical composition for use in preventing or treating cyclosporin A-induced nephrosis.
2) The use according to claim 1, wherein in formula (I) Z is or one of R1, R2, R3 and R4 is -CH2OH, C2-C4 acyl, , -COOR7, -CH2-COOR7, or in which each of R7, R8 and R9 is independently hydrogen or C1-C4 alkyl and the others are hydrogen; and R5 and R6 are hydrogen.
3) The use according to claim 1, wherein the said compound of formula (I) or salt thereof is 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-carboxynaphthalene;
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;
or the pharmaceutically acceptable salts thereof.
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-carboxynaphthalene;
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;
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) (I) wherein a) wherein Y completes a single bond or is oxygen or a -CH2- group and the symbol represents a single or a double bond or (b) is and the symbol --- represents a double bond;
one of R1, R2, R3 and R4 is -CH2OH, C2-C4 acyl, , -COOR7, -CH2-COOR7, , or 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; and (2) a pharmaceutical composition comprising cyclosporin A as active agent.
one of R1, R2, R3 and R4 is -CH2OH, C2-C4 acyl, , -COOR7, -CH2-COOR7, , or 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; and (2) a pharmaceutical composition comprising cyclosporin A as active agent.
5) 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) (I) wherein a) wherein Y completes a single bond or is oxygen or a -CH2- group and the symbol represents a single or double bond or (b) is and the symbol --- represents a double bond;
one of R1, R2, R3 and R4 is -CH2OH, C2-C4 acyl, , -COOR7, -CH2-COOR7, , or 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 accpetable salt thereof; and (2) a pharmaceutical composition comprising cyclosporin A as active agent.
one of R1, R2, R3 and R4 is -CH2OH, C2-C4 acyl, , -COOR7, -CH2-COOR7, , or 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 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 salt thereof is as defined in claim 2 or 3.
7. A kit according to claim 5, wherein the said compound of formula (I) or salt thereof is 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB898914525A GB8914525D0 (en) | 1989-06-23 | 1989-06-23 | Combined use of n-imidazolyl derivatives of bicyclic compounds and cyclosporine in therapy |
| GB8914525.4 | 1989-06-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2035032A1 true CA2035032A1 (en) | 1990-12-24 |
Family
ID=10658992
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002035032A Abandoned CA2035032A1 (en) | 1989-06-23 | 1990-06-25 | Combined use of n-imidazolyl derivatives of bicyclic compounds and cyclosporine in therapy |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0433427A1 (en) |
| JP (1) | JPH04500375A (en) |
| KR (1) | KR920700669A (en) |
| AU (1) | AU636898B2 (en) |
| CA (1) | CA2035032A1 (en) |
| GB (1) | GB8914525D0 (en) |
| HU (1) | HUT55989A (en) |
| IE (1) | IE902266A1 (en) |
| IL (1) | IL94765A0 (en) |
| MY (1) | MY105822A (en) |
| PT (1) | PT94464A (en) |
| WO (1) | WO1991000102A1 (en) |
| ZA (1) | ZA904882B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL91542A0 (en) * | 1988-10-06 | 1990-04-29 | Erba Carlo Spa | N-imidazolyl-and n-imidazolyl-methyl derivatives of substituted bicyclic compounds,their preparation and pharmaceutical compositions containing them |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2141705B (en) * | 1983-06-20 | 1986-09-24 | Erba Farmitalia | Imidazoles |
| EP0300675A3 (en) * | 1987-07-21 | 1990-04-11 | Merck Frosst Canada Inc. | Method for the improvement of cyclosporine therapy |
-
1989
- 1989-06-23 GB GB898914525A patent/GB8914525D0/en active Pending
-
1990
- 1990-06-18 IL IL94765A patent/IL94765A0/en unknown
- 1990-06-22 MY MYPI90001063A patent/MY105822A/en unknown
- 1990-06-22 ZA ZA904882A patent/ZA904882B/en unknown
- 1990-06-22 IE IE226690A patent/IE902266A1/en unknown
- 1990-06-22 PT PT94464A patent/PT94464A/en not_active Application Discontinuation
- 1990-06-25 JP JP2509951A patent/JPH04500375A/en active Pending
- 1990-06-25 HU HU905625A patent/HUT55989A/en unknown
- 1990-06-25 EP EP90910697A patent/EP0433427A1/en not_active Withdrawn
- 1990-06-25 CA CA002035032A patent/CA2035032A1/en not_active Abandoned
- 1990-06-25 AU AU59584/90A patent/AU636898B2/en not_active Ceased
- 1990-06-25 KR KR1019910700200A patent/KR920700669A/en not_active Application Discontinuation
- 1990-06-25 WO PCT/EP1990/001010 patent/WO1991000102A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| KR920700669A (en) | 1992-08-10 |
| JPH04500375A (en) | 1992-01-23 |
| AU636898B2 (en) | 1993-05-13 |
| EP0433427A1 (en) | 1991-06-26 |
| IE902266A1 (en) | 1991-01-16 |
| IL94765A0 (en) | 1991-04-15 |
| HU905625D0 (en) | 1991-06-28 |
| PT94464A (en) | 1991-02-08 |
| WO1991000102A1 (en) | 1991-01-10 |
| ZA904882B (en) | 1992-02-26 |
| AU5958490A (en) | 1991-01-17 |
| GB8914525D0 (en) | 1989-08-09 |
| HUT55989A (en) | 1991-07-29 |
| MY105822A (en) | 1995-01-30 |
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| FZDE | Discontinued |