AU5958490A - 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
- AU5958490A AU5958490A AU59584/90A AU5958490A AU5958490A AU 5958490 A AU5958490 A AU 5958490A AU 59584/90 A AU59584/90 A AU 59584/90A AU 5958490 A AU5958490 A AU 5958490A AU 5958490 A AU5958490 A AU 5958490A
- Authority
- AU
- Australia
- Prior art keywords
- hydrogen
- imidazolyl
- formula
- compound
- alkyl
- 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.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims description 39
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
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- WRMDZKWCUFEOTK-UHFFFAOYSA-N (7-imidazol-1-yl-5,6-dihydronaphthalen-2-yl)methanol Chemical compound C=1C2=CC(CO)=CC=C2CCC=1N1C=CN=C1 WRMDZKWCUFEOTK-UHFFFAOYSA-N 0.000 claims description 2
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- IESWQDIPOXHNKY-UHFFFAOYSA-N 6-imidazol-1-ylnaphthalene-2-carboxylic acid Chemical compound C1=CC2=CC(C(=O)O)=CC=C2C=C1N1C=CN=C1 IESWQDIPOXHNKY-UHFFFAOYSA-N 0.000 claims description 2
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- 238000000605 extraction Methods 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
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- 229960005150 glycerol Drugs 0.000 description 1
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- 229940125721 immunosuppressive agent Drugs 0.000 description 1
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- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
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- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
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- 229940068965 polysorbates Drugs 0.000 description 1
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- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
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- DZUXGQBLFALXCR-CDIPTNKSSA-N prostaglandin F1alpha Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1CCCCCCC(O)=O DZUXGQBLFALXCR-CDIPTNKSSA-N 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- PDQZCMMDLQBNEF-UHFFFAOYSA-M sodium;7-imidazol-1-yl-5,6-dihydronaphthalene-2-carboxylate Chemical compound [Na+].C=1C2=CC(C(=O)[O-])=CC=C2CCC=1N1C=CN=C1 PDQZCMMDLQBNEF-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
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- 238000013222 sprague-dawley male rat Methods 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
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- 239000003765 sweetening agent Substances 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
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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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Transplantation (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Description
COMBINED USE OF N-IMIDAZOLYL DERIVATIVES OF BICYCLIC
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. 99, 851 (1983); Lancet 1, 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 (TxA2) is a potential mediator of altered hemodynamics.
TxA2, 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 TxA2 synthesis has recently been associated with the
immunologically mediated renal injury characteristic of murine 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, 18, 566 (1983) and Transplantation 38, 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 TxA2 (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.
The N-imidazolyl derivatives, according 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 -CH2- group and the symbol ┄ represents a single or a double bond or (b)
and the symbol ┄ represents a double bond;
one of R1, R2, R3 and R4 is -CH2OH, C2-C4 acyl,
in vhich 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.
Preferred compounds of formula (I) are those wherein Z is
one of R , R , R and R4 is -CH2OH, C2-C4 acyl,
-
R9 is independently hydrogen or C1-C4 alkyl, and the others are hydrogen andR5 and R6 are hydrogen; and the pharmaceutically acceptable salts thereof.
Examples of preferred compounds of formula (I) are the following:
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-carboxynaphthaiene;
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 C1-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 C1-C6 alkyl group may be a C1-C4 alkyl group.
Preferably the alkyl group is methyl or ethyl. A C1-C4 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
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, 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.
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 housed and normally fed. The orientative acute toxicity (LD50) 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, preferably from about 200 mg to about 400 mg per dose 1 to 3 times a day. The exact dosage depends on the age, weight, condition of the patient and administration route.
Cyclosporin A and a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered in a variety of dosage forms, e.g., orally, in the form of tablets, capsules, sugar, or film coated tablets, liquid solutions or suspensions; rectally, in the form of suppositories; parenterally, e.g. intramuscularly; or by intravenous injection or infusion.
The present invention also provides a kit comprising in separate containers (1) a pharmaceutical composition containing an effective amount of a compound of formula (I), as
herein defined, or a pharmaceutically acceptable salt thereof, as active ingredient, and (2) a pharmaceutical composition containing an effective amount of cyclosporin A as active ingredient.
The pharmaceutical compositions can be usually prepared following conventional methods and administered in a pharmaceutically suitable form.
For example, the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g.
starches, arable gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used 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 saccharose with gly
cerine and/or mannitol and/or sorbitol.
The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g., propylene glycol, and if desired, 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 compound a pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant 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. 1,2-dihydro-3-(1-imidazolyl)-6-carboxynaphthalene, internal code FCE 22178, 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 -20ºC until the extraction and the radio- immunoassay (RIA) for thromboxane (TX) B2, 6-keto-prostaglandin F1α (PGF1α), and prostaglandin (PG) E2, which reflects the renal synthesis of TXA2, prostacyclin (PGl2), and PGE2, respectively, was performed. Blood samples for determination
of serum TXB2 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 administration of compound FCE 22178 markedly inhibited TXA2 synthesis (measured as TXB2 levels) in whole blood and reduced the significant increase of TXB2- urinary 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:
Compositions (for 10,000 tablets)
1,2-dihydro-3-(1-imidazolyl)-6-carboxynaphthalene 1000 g
Lactose 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 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) 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 Cocoa butter 1.76 g
Total 2.00 g
Claims (10)
1) The use of a compound of formula (I)
wherein wherein Y completes a single
bond or is oxygen or a -CH2- group and the symbol represents a single or a double bond or
and the symbol represents a double bond;
one of R1, R2, R3 and R4 is -CH2OH, C2-C4 acyl,
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 -COOR 7 wherein R7. is as defined above ; and one of R5 and R 6 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-induoed nephrosis.
2 ) The use according to claim 1, wherein in formula (I)
Z is
one of R1 , R2, R3 and R4 is -CH2OH , C2-C4 acyl , in which each of R 7, R8 and
R9 is independently hydrogen or C1-C4 alkyl, and the others are hydrogen. andR5 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.
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)
wherein Y completes a single
bond or is oxygen or a -CH2- group and the symbol represents a single or a double bond or
and the symbol represents a double bond;
one of R1, R2, R3 and R4 is -CH2OH, C2-C4 acyl. 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)
wherein wherein Y completes a single
bond or is oxygen or a -CH2- group and the symbol represents a single or double bond or
and the symbol ┄ represents a double bond;
one of R1, R2, R3 and R4 is -CH2OH, C2-C4 acyl,
in which each of R?, Rg 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 | 1989-06-23 |
Publications (2)
Publication Number | Publication Date |
---|---|
AU5958490A true AU5958490A (en) | 1991-01-17 |
AU636898B2 AU636898B2 (en) | 1993-05-13 |
Family
ID=10658992
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU59584/90A Ceased AU636898B2 (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 PT PT94464A patent/PT94464A/en not_active Application Discontinuation
- 1990-06-22 MY MYPI90001063A patent/MY105822A/en unknown
- 1990-06-22 IE IE226690A patent/IE902266A1/en unknown
- 1990-06-22 ZA ZA904882A patent/ZA904882B/en unknown
- 1990-06-25 KR KR1019910700200A patent/KR920700669A/en not_active Application Discontinuation
- 1990-06-25 CA CA002035032A patent/CA2035032A1/en not_active Abandoned
- 1990-06-25 HU HU905625A patent/HUT55989A/en unknown
- 1990-06-25 AU AU59584/90A patent/AU636898B2/en not_active Ceased
- 1990-06-25 JP JP2509951A patent/JPH04500375A/en active Pending
- 1990-06-25 EP EP90910697A patent/EP0433427A1/en not_active Withdrawn
- 1990-06-25 WO PCT/EP1990/001010 patent/WO1991000102A1/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
HUT55989A (en) | 1991-07-29 |
AU636898B2 (en) | 1993-05-13 |
GB8914525D0 (en) | 1989-08-09 |
IL94765A0 (en) | 1991-04-15 |
MY105822A (en) | 1995-01-30 |
ZA904882B (en) | 1992-02-26 |
PT94464A (en) | 1991-02-08 |
EP0433427A1 (en) | 1991-06-26 |
WO1991000102A1 (en) | 1991-01-10 |
CA2035032A1 (en) | 1990-12-24 |
IE902266A1 (en) | 1991-01-16 |
JPH04500375A (en) | 1992-01-23 |
HU905625D0 (en) | 1991-06-28 |
KR920700669A (en) | 1992-08-10 |
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