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WO1993019066A1 - Derive de l'imidazopyridine et medicament - Google Patents

Derive de l'imidazopyridine et medicament Download PDF

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Publication number
WO1993019066A1
WO1993019066A1 PCT/JP1993/000309 JP9300309W WO9319066A1 WO 1993019066 A1 WO1993019066 A1 WO 1993019066A1 JP 9300309 W JP9300309 W JP 9300309W WO 9319066 A1 WO9319066 A1 WO 9319066A1
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WO
WIPO (PCT)
Prior art keywords
tert
butyl
compound
acid
hydroxy
Prior art date
Application number
PCT/JP1993/000309
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English (en)
Japanese (ja)
Inventor
Shoji Yasufuku
Asahiko Motonaga
Original Assignee
Nippon Shinyaku Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nippon Shinyaku Co., Ltd. filed Critical Nippon Shinyaku Co., Ltd.
Publication of WO1993019066A1 publication Critical patent/WO1993019066A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom

Definitions

  • the present invention relates to an imidazo [1,2-a] viridine derivative represented by the following general formula [I] and a pharmacologically acceptable salt thereof.
  • R 1 represents hydrogen or alkyl
  • R a and R a are the same or different and represent chromium, alkyl, hydroxy, alkoxy, or halogen
  • X represents hydrogen, hydrogen, logene or alkoxy.
  • the present invention relates to a compound in the above formula [I], wherein RR ⁇ R 3 is hydrogen and X is hagen, in particular, odo.
  • the compound of the present invention is useful for rheumatoid arthritis.
  • Rheumatoid arthritis is an autoimmune disease that begins with pain in the peripheral small joints of the extremities and spreads to large joints in the trunk, inflammation of joint slips and destruction of joint tissues. .
  • Prostaglandin which is produced from arachidonic acid by cyclooxygenase, is regarded as a mediator of inflammation and plays an important role in inflammation.
  • Rubilin indomethacin which is widely used as a stabilizing anti-inflammatory pain agent, inhibits cyclooxygenase, and therefore biosynthesis of brostaglandin (PG), toxinboxane (TX), etc. By reducing the amount, anti-inflammatory and spear pain effects can be obtained.
  • LTB 4 leukotrienes (LTs) produced from arachidonic acid by lipoxygenase have been emphasized in relation to bronchial asthma rather than inflammation.
  • LTB 4 has potent polymorph ⁇ leukocyte migration action, since such that there is the effect of increasing the active oxygen production, the importance of re Pokishigena peptidase g path is noted in inflammatory reactions.
  • Dual insulin inhibitors Drugs that inhibit both cyclooxygenase and lipoxygenase, called dual insulin inhibitors, are being sought to be used as more potent anti-inflammatory thorns in the treatment of rheumatoid arthritis. ing.
  • ⁇ 0/89/03833 International Publication discloses that a compound having the same basic skeleton as the compound of the present invention described later has a bone resorption inhibiting action and is effective for osteoporosis. No disclosure is made, and there is no mention of a therapeutic effect on rheumatoid arthritis based on the specific effects of the compound of the present invention (to be described later, “double effect (doubling effect)”). JP-A 61-152681 describes that a compound similar to the compound of the present invention has antithrombotic and cardiotonic effects. However, the compound of the present invention has a therapeutic effect on rheumatoid arthritis based on a dual effect. There is no mention of.
  • non-steroid anti-inflammatory drugs in the treatment of rheumatoid arthritis, non-steroid anti-inflammatory drugs, immunomodulators, anti-inflammatory drugs, immunosuppressants, steroids, etc. are used according to the symptoms.
  • the present inventors have found that they have an effect of suppressing inflammation and having an excellent inhibitory effect on joint destruction, and exhibiting a synergistic effect due to the simultaneous occurrence of these two actions.
  • Research was conducted to obtain a new type of chronic orchid rheumatoid arthritis drug.
  • the present inventors have referred to this synergistic effect as “double effect” and have devoted themselves to the discovery of a drug having this double effect.
  • Japanese Patent Application Laid-Open No. 3-77894 describes that a methylene diphosphonic acid compound has both an anti-inflammatory action and an inhibitory action on bone bone and is effective for arthritis and the like.
  • the double effect cannot be said to have been originally proposed by the present inventors, the effect disclosed here is not strong enough to be put to practical use, and a synergistic effect caused by the simultaneous occurrence of the two effects.
  • No double effect according to the present invention is intended for the first time by the present invention, since no specific effect is mentioned. O
  • the gist of the present invention lies in the structure itself of the compound represented by the general formula [I].
  • the alkyl represented by R 3 or 3 is preferably a straight-chain or branched K-type alkyl group having 1 to 4 amino acids, such as methyl and ethyl. , N-propyl, isoprovir, ⁇ -butyl, sec-butyl, tert-butyl and the like.
  • the alkoxy represented by R 3, R a lay preferred linear or branched techniques like low ⁇ alkoxy carbon number 1-4, for example, main butoxy, E butoxy, n- propoxy, i Sopu Poxy, n-butoxy, isobutoxy, sec-butoxy and the like can be mentioned.
  • halogen represented by R 2 and R 3 examples include chlorine, bromine, fluorine, iodine and the like.
  • halogen represented by "include chlorine, bromine, fluorine, iodine, and the like.
  • the alkoxy represented by X is preferably a straight-chain or branched low-working alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy, ⁇ -butyl ⁇ -poxy, isopropoxy, ⁇ - Butoxy, isobutoxy, sec-butoxy and the like.
  • the structural features of the compound of the present invention are: (1) having imidazo [l, 2-a] pyridine skeleton; and (2) the imidazo [1, 2-a] pyridine skeleton has a tert- S-substituted with butyl-4-hydr ⁇ -xyphenyl group, (3) The above 3-tert-butyl-4-hydr ⁇ -xyphenyl group is either anonymous or substituted with halogen or alkoxy.
  • the structural features of the present invention include, in addition to the above 1, 2, and 3, the imidazo [1,2-a] pyridine skeleton of 2 above has a g ⁇ group in addition to 1 There is no thing.
  • a structural feature of the compound of the present invention is that, in the above 3, the 5-position of the 3-tert-butyl-4-hydroxyphenyl group is substituted by a halogen, particularly a halide.
  • the compound of the present invention having the above structural characteristics is a novel compound not described in the literature, exhibits excellent pharmacological action as described below, and has low toxicity.
  • the aforementioned 2- (3,5-di-tert-butyl-4-hydroxyhydroxynyl) imidazo [1,2-a] pyridine has an inhibitory effect on power-lagenin edema and an effect on adjuvant arthritis.
  • it does not have an IL-1 release inhibitory action, and thus cannot attain the pharmacological action by the double effect aimed at by the present invention.
  • the gastric mucosa has a very strong harmful effect, so that it cannot be put to practical use.
  • imidazo [1,2-a] bili The phenyl substituted at the 2-position of the gin skeleton has hydroxy as a 4-position substituent, a tert-butyl group as a 3-position substituent, and a penta- or 5-position substituent. Is thought to be due to having an alkoxy or not having a g-substituent at the 5-position.
  • the double effect of the compound of the present invention is that the compound of the present invention has a chemical structure in which the halogen substituted as the 5-position substituent of phenyl substituted to the 2-position of the above imidazo [1,2-a] viridine skeleton.
  • the manifestation of having an evil is not continuous.
  • the compound of the present invention can be produced, for example, by the following method:
  • RR 3 , R 3 and X are the same as above, and Z represents a halogen.
  • a base or [I] can be produced by reacting in the absence of 0 to 150, preferably 0 to 100.
  • the reaction solvent include alcohols such as methanol, ethanol, and isopropyl alcohol; hydrated carbons such as benzene and toluene; dioxane; ethers such as 1,2-dimethoxyethane; Acetonitrile, ⁇ , ⁇ -dimethylformamide and the like can be used.
  • the base include inorganic salts such as alkaline hydrogen carbonate (eg, sodium hydrogen carbonate) and carbonates (eg, potassium carbonate).
  • An organic base such as a group or triethylamine can be used.
  • H varies depending on the raw materials, the type of solvent and the type of base used, but usually 1 to 24 hours is appropriate. It is preferable that the amount of the 2-minobilizins used is at least equimolar to [II]. In addition, the reaction may be carried out using surplus 2-amino minopyridines instead of the above bases. In this case, it is generally preferable to use 2-amino viridines in an amount of 2 mol / l to 1 mol of [II].
  • the starting material [II] will be described as a reference example, but can be produced as follows.
  • a silylating agent for example, anhydrous acetic acid, acetyl chloride
  • a suitable base for example, viridine
  • 2-tert-butylphenol is used.
  • solvents or inert solvents eg benzene, toluene Hydrocarbons such as ethylene, ethers, ethers such as tetrahydrofuran, dioxane, halogen solvents such as ⁇ -form, methylene chloride, or N-dimethylformamide. Reaction yields 2-acetyloxy-tert-butylbenzene.
  • 2-tert-butyl-4-acylphenol can be obtained by reacting with 0-30 t.
  • This compound is prepared by combining 2-tert-butylphenol and a acylating agent (eg, acetylk D-lide) in an inert solvent, preferably 1,2-dichloromethane, in the presence of lewis acid. It can also be obtained by reacting at 0 to 30 t.
  • the present compound can be synthesized in addition to the above, for example, as follows. .
  • the target compound [I] and the intermediate produced in this manner can be produced in a form of a free base or an acid addition salt by means known per se, for example, concentration, liquid conversion, phase transfer, It can be purified simply by solvent extraction, crystallization, recrystallization, fractionation, chromatography, etc.
  • examples of the ⁇ I acid • 1 addition salt of the compound represented by the general formula [I] include salts of base acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; Salts of organic acids such as carboxylic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid and the like can be mentioned.
  • the compound of the present invention when administered as a medicament, the compound of the present invention may be used as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example,
  • composition containing 0.1% to 99.5, preferably 0.5X to 9DX.
  • the pharmaceutical composition is administered It is desirable to administer in units.
  • the pharmaceutical composition of the present invention can be administered intravenously, orally, intraosseously, topically (eg, *, ophthalmic) or rectally. Needless to say, it is administered in a type III suitable for these administration methods. Perot administration is particularly preferred.
  • the amount of the active ingredient of the present invention is generally in the range of 1 (! To 1500 ing / hit, preferably in the range of 50 to 600 rag / hit. The following are sufficient, and conversely, may require higher doses, and may be given in 2 to 4 divided doses per day.
  • Perforation is performed in solid or liquid dosage units such as powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, tablets, sublingual tablets, etc. Can be carried out depending on the dosage form.
  • Powders are prepared by comminuting the active substance to an appropriate degree. Powders are prepared by comminuting the active substance with an appropriate degree of fineness and then with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate such as starch, mannitol. Flavoring agents, preservatives, dispersing agents, coloring agents, fragrances and other substances may be mixed as necessary.
  • Forcepsel II is prepared by first converting powdered powders, powders, or granules as described in the section on tablets into a forcepsell shell such as a gelatin capsule. It is manufactured by filling.
  • Lubricants and glidants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid poly 00309
  • Disintegrators and solubilizers for example, carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropyl mouth cellulose, croscarmester sodium, carboxystarch sodium, calcium carbonate, sodium carbonate
  • croscarmester sodium for example, carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropyl mouth cellulose, croscarmester sodium, carboxystarch sodium, calcium carbonate, sodium carbonate
  • the powder of this product can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant, and wrapped in a gelatin sheet to prepare a soft capsule.
  • Tablets are made by preparing a powder mixture, granulating or slugging, then adding a disintegrant or lubricant and pressing.
  • the powder mixture is obtained by mixing an appropriately powdered substance with the above-mentioned diluent or paste and, if necessary, a binder (eg, carboxymethylcellulose sodium, hydroxybile, virucellulose, methylcellulose, hydroxyb).
  • the powder mixture can be moistened with a binder, for example, syrup, powdered glue, gum arabic, cellulose solution or polymer solution, and then forced through a sieve to form granules.
  • a binder for example, syrup, powdered glue, gum arabic, cellulose solution or polymer solution
  • lubricating agents such as stearic acid, stearate, talc, mineral oil, etc.
  • the material thus manufactured can be coated with a film coating or sugar coating.
  • the drug may be directly compressed into tablets after mixing with a flowable inert carrier without going through the steps of granulation and slag formation as described above.
  • a transparent or translucent protective coating consisting of a hermetically sealed shinac coating, a coating of sugar molecular material, and a top coating consisting of wax can also be used.
  • oral dosage forms such as solutions, syrups and elixirs
  • Syrup is produced by dissolving the compound in an appropriate aqueous flavor solution
  • elixir is produced by using a non-toxic alcoholic carrier.
  • the agent is formulated by dispersing the compound in a toxic carrier.
  • Solubilizers and emulsifiers eg, ethoxylated isosteryl alcohols, polyoxyethylene sorbitol esters
  • preservatives eg, palmit oil, saccharin
  • flavor enhancers eg, palmit oil, saccharin
  • the dosage unit formulation for microdose administration can be microbubulated.
  • the tatami formula can also provide a prolonged duration of action or sustained release by coating or embedding in polymers, waxes, etc.
  • Intra-therapeutic administration is for subcutaneous, intramuscular or intravenous injection. It can be done in dosage unit form, for example, in the form of solutions or SIS agents. These are accomplished by suspending or dissolving a fixed amount of the compound in a non-toxic liquid carrier suitable for the purpose of injection, such as a permanent or oily medium, and then sterilizing the suspension or solution. Manufactured. Alternatively, an aliquot of the compound may be placed in a vial, and the vial and its contents sterilized and sealed thereafter. Spare vials or carriers may be provided with the powdered or * dried active ingredient for dissolving or mixing immediately prior to administration. Non-toxic salts or salt solutions may be added to make the injection solution isotonic. Further, stabilizers, preservatives and emulsifiers can be used in combination.
  • Rectal administration involves mixing the compound with a low-touch-point water-soluble or insoluble facet, such as polyethylene glycol, cocoa butter, esters (eg, myristyl palmitate), and mixtures thereof. This can be done by using suppositories.
  • a low-touch-point water-soluble or insoluble facet such as polyethylene glycol, cocoa butter, esters (eg, myristyl palmitate), and mixtures thereof. This can be done by using suppositories.
  • the compound of Example 2 had a much better pharmacological effect than the other compounds represented by the general formula [I]. When examining the double effect, the other compound had an inferior effect as compared with the compound of Example 2.
  • the present invention relating to the compound of Example 2 has been completed only by encountering this fact.
  • the present invention provides a compound represented by the general formula [I]: RR 2 , R a is Korimoto, and, X is established only compounds which are Yodo.
  • the compound of the present invention Since the compound of the present invention has both an anti-inflammatory effect and an inhibitory effect on joint destruction (an inhibitory effect on bone resorption and an inhibitory effect on plasma membrane proliferation) and low toxicity, it is useful for chronic joint I) It can be used for the improvement of inflammatory symptoms such as osteoarthritis, osteoarthritis, pain pain, juvenile inflammation, cervical dystrophy, and pain. In addition, it has an antiallergic effect, so it can be used to improve allergic symptoms such as bronchial asthma, chronic mushroom measles, allergic * flame, and Toby dermatitis. It is a safe drug because it has few side effects such as gastrointestinal disorders and low toxicity.
  • This compound can also be produced as follows.
  • Step 4 Dissolve 8.56fif of 3'-bromo-4'-hydroxy-5, -tert-butylacetatephenone in 150 ral of polyester and, at room temperature with stirring, convert 5.1 g of bromine to 50 nl of ether. Dissolve and drip.
  • the reaction mixture is stirred at room temperature for another hour.
  • the ether shield was removed, washed with water, sodium hydrogen sulfite, and water, and dried over magnesium sulfate.
  • the solvent was distilled off to obtain 11.2 g of 2,3′-dibu ⁇ -mo-5′-tert-butyl-4′-hydroxyacetophenone as a pale brown oil.
  • Method b 34.5 g of 3'-tert-butyl-4'-hydroxy-terminated pentanone is dissolved in 520 ml of ethanol, and 22.76 g of iodine is added. Then dissolve 3g of iodic acid in 170ml of water and add 60 ⁇ ? For 3 hours and released overnight. Ethanol was distilled off, and the residue was dissolved in ft-ethyl acetate. The ethyl acetate solution was washed with water, washed with sodium thiosulfate ice solution, washed again for a long time, and dried with magnesium sulfate.
  • Method b 3'-tert-butyl-4'-hydroxy-5, -method
  • a mixture of 21.96 g, 20% of an il% hydrogen fluoride-extended ice solution and 300 ml of clog mouth form was added dropwise with lg of bromine at an external temperature of 20 over 45 minutes, followed by drying at the same temperature for 1.5 hours.
  • the reaction solution was washed with water, washed with an aqueous solution of sodium thiosulfate, washed again with water, and baked with magnesium triluate.
  • the solvent was distilled off to obtain 29.6 g of 2-promote-3'-tert-butyl-4'-hydroxy-5, -thiophene.
  • Kazutoshi point 183-184 - elemental analysis planting (as C ie H 2O N 2 0 2 )
  • DMBM 103 ⁇ 4 calf serum containing Darube' co variant b Guru ⁇ solution
  • the compound of the present invention has a brostaglandin biosynthesis inhibitory action equal to or higher than that of the control drug, and is expected to have an anti-inflammatory action.
  • HBPBS [N- (2-hydroxyxetil) bidirazine-N, -2-ethanesulfonic acid]
  • the compound of the present invention has an active oxygen production inhibitory effect that is 50 times or more superior to that of the control drug.
  • the compound of the present invention has an excellent 5-lipoxygenase inhibitory activity not found in the control drug.
  • the compound of the present invention has an excellent bone resorption inhibitory action not found in the control drug.
  • Chronic ⁇ Li Umachi patient Namera ⁇ cells (10 4) were cultured in I Ll (100pg / ffll) and Dulbecco's modified method Iguru medium containing the test drug (10X calf serum-containing), a K-th time 66 a H-thymidine (18.5 kBq) was added, and the cells were further cultured for 6 hours. After completion of the culture, the radioactivity of 3 H-thymidine incorporated into synovial cells was measured. Table 5 shows the results.
  • the compound of the present invention has an excellent inhibitory action on the growth of human slip which is not seen in the control drug.
  • test drug was orally administered once a day from the first cropping day until the 34th day for 35 days.
  • Example 2 suppressed all items, and the minimum effective dose was lOrag / kg.
  • mice Male rats (SD strain, 6-week-old) were grouped into 6 rats, each of which was used at 24 hours before the administration of the test drug.
  • the test drug was dissolved or suspended in an ice solution of methylcellulose and administered in a syringe. Seven hours after administration of the test drug, the stomach was removed, 10 ml of formalin solution was injected into the stomach, and the stomach was immersed in ⁇ formalin solution and fixed. Ten minutes after formalin fixation, the stomach was dissected along the bay and the stomach was observed using a stereomicroscope. Table 6 shows the results. Table 6
  • the compound of the present invention can be said to be a drug with very little damage to the gastric mucosa and little risk of side effects.
  • Mononuclear cells were separated from healthy human peripheral blood by the PicoU-Hypaque overlay method, dispersed in RPMI-1640 culture broth, and then seeded on a 96-well culture plate at 2xlO s. did. Two hours later, each well was washed with RPMI-1640 to remove non-adherent cells, and the adherent cells were subjected to the experiment. The drug and RPMI-1640 supplemented with 2% calf serum were added to each well, and cultured for 1 hour. Then, lipopolysaccharide (1 (g / ml) was added. After culturing for 16 hours, the culture supernatant was collected and IL-1 contained therein was quantified by a sodium immunoassay. Table 7 shows the results. Table 7
  • the comparative compound has no inhibitory effect on IL-1 release, it is clear that the compound of the present invention has an inhibitory effect on IL-1 migration and contributes to an inhibitory effect on joint destruction.
  • the comparative compound has a clear gastric mucosal damage effect and cannot be used as a pharmaceutical.
  • the compounds of the present invention are not only effective in inhibiting inflammation, but also have a good balance of cyclooxygenase and lipoxygenase activity inhibitory effects, and are known as existing anti-inflammatory agents.
  • No inhibitory effect on IL-1 migration, inhibitory effect on synovial growth and bone resorption by IL-1 It can be seen that it has an action (section ⁇ inhibitory action).
  • it has an inhibitory effect on the production of active oxygen by polymorphonuclear leukocytes, and thus can stop the progression of rheumatoid arthritis.
  • it suppresses arthritis induced by adjuvant or type II collagen and has few side effects such as gastrointestinal disorders, so it can be safely used for chronic rheumatoid arthritis.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On décrit un dérivé de l'imidazo[1,2-a]pyridine, et un de ses sels acceptables sur le plan pharmacologique, correspondant à la formule (I) où R1 représente hydrogène ou alkyle; R2 et R3, qui peuvent être identiques ou différents, représentent chacun alkyle, hydroxy, alcoxy ou halogène; et X représente hydrogène, halogène ou alcoxy. Ce composé n'est pas seulement utile pour lutter contre l'inflammation mais il permet aussi, contrairement aux agents anti-inflammatoires actuels, d'enrayer la destruction des articulations, et se révèle donc efficace dans le traitement de l'arthrite rhumatoïde.
PCT/JP1993/000309 1992-03-17 1993-03-16 Derive de l'imidazopyridine et medicament WO1993019066A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP9197192 1992-03-17
JP4/91971 1992-03-17
JP4/146236 1992-05-12
JP14623692 1992-05-12
JP4/183128 1992-06-16
JP18312892 1992-06-16

Publications (1)

Publication Number Publication Date
WO1993019066A1 true WO1993019066A1 (fr) 1993-09-30

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MX (1) MX9301458A (fr)
WO (1) WO1993019066A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0668278A1 (fr) * 1994-02-19 1995-08-23 MERCK PATENT GmbH Antagonistes du récepteur d'adhésion
WO2000008024A1 (fr) * 1998-08-03 2000-02-17 Laboratorios S.A.L.V.A.T., S.A. Imidazo[1,2a]azines substituees servant d'inhibiteurs selectifs de la cox-2
US7375236B2 (en) 2003-02-19 2008-05-20 Eisai Co., Ltd. Methods for producing cyclic benzamidine derivatives

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991000092A1 (fr) * 1989-06-13 1991-01-10 Smithkline Beecham Corporation Inhibition de la production d'interleukine-1 et du facteur de necrose de tumeurs par l'utilisation de monocytes et/ou de macrophages

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991000092A1 (fr) * 1989-06-13 1991-01-10 Smithkline Beecham Corporation Inhibition de la production d'interleukine-1 et du facteur de necrose de tumeurs par l'utilisation de monocytes et/ou de macrophages

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEM. PHARM. BULL., Vol. 31, No. 9, (1983), YASUO ISOMURA AND OTHERS, "Studies on the Synthesis and Antiinflammatory Activity of 2,6-Di-Tert-Butylphenols with a Heterocyclic Group at the 4-Position", pp. 3168-3178. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0668278A1 (fr) * 1994-02-19 1995-08-23 MERCK PATENT GmbH Antagonistes du récepteur d'adhésion
US5614531A (en) * 1994-02-19 1997-03-25 Merck Patent Gesellschaft Mit Beschrankter Haftung Adhesion receptor antagonists
WO2000008024A1 (fr) * 1998-08-03 2000-02-17 Laboratorios S.A.L.V.A.T., S.A. Imidazo[1,2a]azines substituees servant d'inhibiteurs selectifs de la cox-2
US7375236B2 (en) 2003-02-19 2008-05-20 Eisai Co., Ltd. Methods for producing cyclic benzamidine derivatives

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AU3648993A (en) 1993-10-21

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