WO1999020618A1 - Amides thiadiazoles utiles comme anti-inflammatoires - Google Patents

Amides thiadiazoles utiles comme anti-inflammatoires Download PDF

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Publication number
WO1999020618A1
WO1999020618A1 PCT/US1998/021629 US9821629W WO9920618A1 WO 1999020618 A1 WO1999020618 A1 WO 1999020618A1 US 9821629 W US9821629 W US 9821629W WO 9920618 A1 WO9920618 A1 WO 9920618A1
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Prior art keywords
thiadiazol
thio
alkyl
het
substituted
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PCT/US1998/021629
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English (en)
Inventor
Ronald B. Gammill
Susan Vander Velde
Richard Allen Nugent
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Active Biotech Ab
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Priority to AU10834/99A priority Critical patent/AU1083499A/en
Publication of WO1999020618A1 publication Critical patent/WO1999020618A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel thiadiazole amides, to pharmaceutical compositions containing them, and to methods of using them.
  • the compounds of the invention are pharmaceutically active in the treatment of inflammatory diseases.
  • Inflammation is an integral part of a wide array of human diseases, ranging from bacterial pneumonia, in which the response is life-saving, to adult respiratory distress syndrome, in which it is life-threatening. Inflammation may result in substantial tissue damage or initiate processes leading to excessive fibrous repair, and therefore, it is desirable to interrupt its progression.
  • Today, many investigators are attempting to identify new therapeutic agents designed to directly block adhesive events involved in an array of disease processes.
  • LFA-1 and Mac-1 members of the ⁇ 2 integrin family of adhesion molecules, are thought to play a critical role in several types of inflammatory disease processes by interacting with intercellular adhesion molecule (ICAM), which promotes the migration of the leukocyte rapidly into surrounding tissue.
  • ICAM intercellular adhesion molecule
  • blockade of the LFA-1 complex has been shown to inhibit neutrophil influx in almost every system, including skin, peritoneum, synovium, lung, kidney, and heart.
  • thiadiazole amides are LFA-1 and Mac-1 inhibitors. Molecules that inhibit LFA-1 and Mac-1 binding with ICAM-1 down regulate inappropriate leukocyte wreaking havoc on healthy tissues seen in acute and chronic inflammatory diseases. As such, these compounds are therapeutically useful in the treatment of a broad range of inflammatory disease such as, for example, hypersensitivity reactions, asthma, rheumatoid arthritis, bacterial meningitis, aspiration lung injury, inflammatory bowel disorder and related complications.
  • INFORMATION DISCLOSURE The following references disclose thiadiazole derivatives. International Publication No. WO 96/30370 discloses thiazole and thiadiazole derivatives useful in the treatment of thrombocytopenia.
  • U. S. Patent 4,775,408 discloses pyridine substituted thiadiazole ureas which have herbicidal and plant growth regulatory properties.
  • U. S. Patent 4,576,629 discloses herbicidal thiadiazole ureas wherein the 5- position of the thiadiazole ring is hetero substituted and which exhibit enhanced selective herbicidal activity.
  • Abstract of Japanese Patent 1160-976-A discloses 1,3,4-thiadiazole derivatives useful as antiulcer agents.
  • R 3 is a) -(CR 9 R 10 ) r (CH 2 ) r aryl, b) -(CR 9 R 10 ) r (CH 2 ) r aryl wherein aryl is substituted with one to three R ⁇ , c) -(CR 9 R 10 ) r (CH 2 ) r Q, d) -(CR 9 R 10 ).-(CH 2 ) r Q wherein Q is substituted with one to three R n , e) -(CR 9 R 10 ) ; -(CH 2 ) r Het, f) -(CR 9 R 10 ) r (CH 2 ) r Het wherein Het is substituted with one to three R n , or g) -(CR 9 R 10 ) r (CH 2 ) r pentafluorophenyl;
  • R 4 is a) halo, b) C 1-4 alkyl, c) C 3 . 6 cycloalkyl, d) C j . 4 alkoxy, e) aryl, f) Q, g) Het, h) C 1 carboalkoxy, i) C l monoalkylamino, j) C 1A dialkylamino, k) amido,
  • R 5 is a) C s alkyl, b) aryl, c) Q, or d) Het;
  • R 6 is a) halo, b) hydroxy, c) C j _ 4 alkoxy, d) 0 ⁇ 4 carboalkoxy, e) amido, f) nitro, g) trihalomethyl, h) cyano, i) mercapto, j) C j . 4 alkylthio, or k) C j . 8 alkyl;
  • R 7 and R 8 are the same and different a) H, b) C j . 6 alkyl, c) C 3.6 cycloalkyl, d) -(CH ⁇ -O-C ⁇ alkyl, e) -(CH 2 ) r Q, or ) -(CH 2 ) r Het;
  • R 9 and R 10 are the same and different a) H, b) C 1-4 alkyl, c) 0 ⁇ 4 alkoxy, d) C 3.6 cycloalkyl, or e) C x.4 carboalkoxy;
  • R ⁇ is a) C 1 . 4 alkyl, b) Cj. 4 alkoxy, c) trihalomethyl, d) halo, e) nitro, f) cyano, g) nitrine, h) C j . 4 acyl, i) C 1 carboalkoxy, or j) carboxyl;
  • aryl is monocarbocyclic, or bicarbocyclic aromatic moiety;
  • Q is 5- to 10-membered saturated heterocyclic moiety having one to three atoms selected from the group consisting of oxygen, nitrogen, and sulfur;
  • Het is 5- to 10-membered unsaturated heterocyclic moiety having one to three atoms selected from the group consisting of oxygen, nitrogen, and sulfur;
  • h is 0, 1, 2 or 3;
  • i is 0 or 1;
  • j is 0, 1, 2, 3, 4 or 5;
  • k is 0, 1, 2 or 3;
  • I is 0, 1, 2, 3, 4 or 5; n is 0, 1 or 2; and with the following provisos: a) where both R 7 and R 8 are hydrogen, j + k is other than 1; b) where R 3 is phenyl substituted with fluoro, R x is other than unsubstituted phenyl.
  • These compounds are therapeutically useful in the treatment of a broad range of inflammatory disease such as, for example, hypersensitivity reactions, asthma, rheumatoid arthritis, bacterial meningitis, aspiration lung injury, inflammatory bowel disorder and related complications.
  • inflammatory disease such as, for example, hypersensitivity reactions, asthma, rheumatoid arthritis, bacterial meningitis, aspiration lung injury, inflammatory bowel disorder and related complications.
  • the carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C ⁇ defines the number of carbon atoms present from the integer "i" to the integer "j", inclusive.
  • C ⁇ alkyl refers to alkyl of one to four carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof.
  • C 14 alkyl refers to an alkyl group having one to four, one to six, one to eight, or one to ten carbon atoms respectively such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and their isomeric forms thereof.
  • C 2 . 10 alkenyl refers to at least one double bond alkenyl group having two to ten carbon atoms respectively such as, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, heptdienyl, octenyl, octadienyl, octatrienyl, nonenyl, undecenyl, dodecenyl, and their isomeric forms thereof.
  • C 3 refers to at least one double bond alkenyl group having two to ten carbon atoms respectively such as, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, heptdienyl, octenyl, octadienyl, octatrienyl, nonenyl, undecenyl, dodecenyl
  • cycloalkyl refers to a cycloalkyl having three to six carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and their isomeric forms thereof.
  • C M alkoxy refers to an alkyl group having one to four carbon atoms attached to an oxygen atom of hydroxyl group such as, for example, methoxy, ethoxy, propyloxy, butyloxy and their isomeric forms thereof.
  • C alkylthio refers to an alkyl group having one to four carbon atoms attached to an thiohydroxy moiety, for example, methythio, ethylthio, propylthio, butylthio and isomeric forms thereof.
  • C, .4 acyl and “C ⁇ acyl” refer to a carbonyl group having an alkyl group of one to four or one to six carbon atoms respectively.
  • C H carboalkoxy and carboalkoxy refer to an ester group having an alkyl group of one to four or one to six carbon atoms respectively.
  • C 14 monoalkylamino refers to an alkyl group having one to four carbon atoms attached to an amino moiety, for example, methylamine, ethylamine, n-propylamine, n-butylamine, and isomeric forms thereof.
  • C, .4 dialkylamino refers to two alkyl groups having one to four carbon atoms attached to an amino moiety, for example, dimethylamine, methylethylamine, diethylamine, dipropylamine, methypropylamine, ethylpropylamine, dibutylamine, and isomeric forms thereof.
  • halo refers to fluoro, chloro, bromo, or iodo.
  • trihalomethyl refers to trifluoromethyl, trichloromethyl or tribr omomethyl .
  • aryl refers to monocarbocyclic or bicarbocyclic aromatic moiety such as, for example phenyl, naphthyl or biphenyl. Each of these moieties may be substituted as appropriate.
  • Aryl is preferably substituted and unsubstituted phenyl.
  • Het refers to a 5- to 10-membered unsaturated heterocyclic moiety having one or more atoms selected from the group consisting of oxygen, nitrogen, and sulfur such as; for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3- quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2- quinoxalinyl, 1-phthalazinyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-
  • Q refers to a 5- to 10-membered saturated heterocyclic moiety having one to two atoms selected from the group consisting of oxygen, nitrogen, and sulfur such as, for example, piperidinyl, 2-, 3-, or 4-piperidinyl, [l,4]piperazinyl, morpholinyl, 2- or 3-morpholinyl, thiomorpholinyl, dioxolanyl, imidazolidinyl, [l,3]oxathiolanyl, [l,3]oxazolidinyl, pyrrolidinyl, butyrolactonyl, butyrolactamyl, succinimidyl, glutarimidyl, valerolactamyl, 2,5-dioxo-[l,4]-piperazinyl, pyrazolidinyl, 3-oxopyrazolidinyl, 2-oxo-imidazolidinyl, 2,4-dioxo-imidazolidinyl
  • THF tetrahydrofuran
  • DMF dimethyl formamide
  • pharmaceutically acceptable salts refers to addition salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate and the like. These salts may be in hydrated form. Some of the compounds of this invention may form metal salts such as sodium, potassium, calcium and magnesium salts and these are embraced by the term “pharmaceutically acceptable salts.”
  • the compounds of formula I of this invention may contain a chiral center and other isomeric forms and this invention embraces all possible stereoisomers and geometric forms.
  • Typical antiinflammatory thiadiazoles amides of this invention are a. 3-Fluoro-N-[5-[(l-phenylpropyl)thio]-l,3,4-thiadiazol-2-yl]benzeneacetamide, b. (E)-3-Nitro-N-[5-[(3J-dimethyl-2,6-octadienyl)thio]-l,3,4-thiadiazol-2- yl]benzamide, c. (E)-3-Trifluoromethyl-N-[5-[(3J-dimethyl-2,6-octadienyl)thio]-l,3,4-thiadiazol- 2-yl]benzamide, d.
  • R' -halo (A) with commercially available 5-amino-l,2,5-thiadiazole-2-thiol in the presence of appropriate base such as, for example, triethylamine or sodium hydride.
  • R' is Rj-R 2 -radical as defined previously and halo is fluoro, chloro, bromo or iodo.
  • the alkylating agents A are either commercially available or can be prepared from the corresponding alcohols with an activating agents such as methanesulfonyl chloride or thionyl chloride. The coupling results in the formation of the intermediate B
  • Particularly useful starting compounds in the preparation of compounds of formula I of the present invention is a compound of formula D
  • compositions of this invention may be prepared by combining the compounds of formula I of this invention with a solid or liquid pharmaceutically acceptable carrier, and optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques.
  • Solid form compositions include powders, tablets, dispersible granules, capsules and suppositories.
  • a solid carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent.
  • Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like.
  • Liquid form compositions include solutions, suspensions and emulsions.
  • solutions of the compounds of this invention dissolved in water, water-propylene glycol, and water-polyethylene glycol systems, optionally containing conventional coloring agents, flavoring agents, stabilizers and thickening agents.
  • composition is provided by employing conventional techniques.
  • composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula I according to this invention.
  • the quantity of active component, that is, the compounds of formula I according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration.
  • the quantity of the active component will range between 0.5% to 90% by weight of the composition.
  • the compounds or pharmaceutical compositions thereof will be administered orally, parenterally, aerosol, and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antiflammatory effective.
  • a concentration that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antiflammatory effective.
  • such antiinflammatory effective amount of dosage of the active component will be in the range of about 0.1 to about 200 mg kg, more preferably about 3.0 to about 50 mg/kg of body weight/day. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of the inflammatory complication being treated, and the particular compounds being used.
  • the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day.
  • compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compounds according to formula I as a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a suitably buffered isotonic solution having a pH of about 3.5 - 6.0
  • a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a suitably buffered isotonic solution having a pH of about 3.5 - 6.0
  • Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine, to name a few.
  • the compounds according to formula I generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg/ml to about 400 mg/ml.
  • the resulting liquid pharmaceutical composition will be administered so as to obtain the above mentioned antiflammatory effective amount of dosage.
  • the compounds of formula I according to this invention are advantageously administered orally in solid and liquid dosage forms.
  • the compounds of this invention are useful antiinflammatory agents, effective against a broad range of inflammatory disease states in which neutrophils wreak havoc on healthy tissues. Therefore, they are therapeutically useful in the treatment of chronic or acute inflammatory disease such as, for example, hypersensitivity reactions, asthma, rheumatoid arthritis, bacterial meningitis, aspiration lung injury, inflammatory bowel disorder and related complications. Humans or animals suffered with such complications are readily diagnosed by a physician or veterinarian of ordinary skill.
  • the mesylate of the appropriate alcohol is prepared in situ.
  • the alcohol (1 equiv.) is dissolved in THF, and triethylamine (2 equiv.) is added.
  • the reaction is cooled to 0°C, and methanesulfonyl chloride (1.1 equiv.) is added.
  • the reaction is allowed to warm to room temperature. After 1 hour, 5-amino-l,3,4-thiadiazole-2- thiol (1 equiv.) is added.
  • the reaction is stirred overnight.
  • the reaction is diluted with EtOAc and H 2 0. After separation, the aqueous phase is extracted with EtOAc.
  • the combined organics are washed with brine, dried over MgS0 4 , and concentrated to crude material.
  • the product is purified by flash chromatography or recrystallization.
  • the thiadiazole is deprotonated by added sodium hydride (1.1 equiv.) to a 0°C solution of 5-amino-l,3,4-thiadiazole-2-thiol (1 equiv.) and dissolved in DMF.
  • the reaction is allowed to warm to room temperature and stirred overnight.
  • the reaction is quenched and diluted with H 2 0.
  • the aqueous phase is extracted with EtOAc, and the combined organics are washed with brine. After drying over MgS0 4 , the solvent is removed in vacuo yielding crude material.
  • the product is isolated by flash chromatography or recrystallization.
  • Step 1 Preparation of 5-[(l-pyridinylpropyl)thio]-l,3,4-thiadiazol-2-amine. Following the general procedure outlined in Method B and making non- critical variations but starting with 1-phenylpropyl alcohol and 2-amino-5-mercapto- 1,3,4-thiadiazole, the title compound is obtained as a solid. The crude product is purified by flash chromatography (5% CH 3 0H/CH 2 C1 2 ). mp 113-114°C. ⁇ NMR (CDClg) ⁇ 0.94, 1.97-2.15, 4.40, 5.30, 7.25-7.31. 13 C NMR (DMSO) ⁇ 11.8, 28.5, 54.9, 127.5, 127J, 128.4, 140.5, 148.0, 170.4.
  • the compounds may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.
  • two primary and two secondary assays are performed.
  • the assays are established to identify compounds which inhibit the interaction of either LFA-1 or Mac-1 with immobilized ICAM-1.
  • the interaction of the ⁇ 2 integrins with ICAM-1 plays as important role in a number of adhesive events during normal immune and inflammatory responses including antigen presentation to T cells, T cell mediated cytotoxicity, and the firm attachment and extravasation of circulating leukocytes into the surrounding tissue.
  • Both the primary LFA-1 and Mac-1 adhesion assays are performed using the well- known scintillation proximity assay (SPA) bead technology which is discussed in further in Cook, N.D. et. al. Pharmaceutical Manufacturing International (1992) pp.
  • SPA scintillation proximity assay
  • the assay relies upon three major components: a radiolabeled CHO cell that has been transfected with the heterodimeric either LFA-1 or Mac-1 molecule and is functionally expressed on the cell surface; a secreted soluble form of intercellular ahesion molecule produced from a transfected CHO cell line and which has subsequently been biotinylated; and streptavidin SPA beads to monitor the interaction of these two components.
  • the SPA technology is utilized because it obviates the need for a wash step(s), allowing low affinity interactions to remain undisturbed.
  • Stable CHO cells expressing either LFA-1 or Mac-1 were established. Cells were grown in modified Dulbecco's media and labeled overnight in a leucine deficient media in the presence of 3 H-leucine (10 mCi/10 6 cells for LFA-1 and 50 mCi/10 6 cells for Mac-1). After labeling, cells (1 x 10 4 LFA-1 and 5 x 10 4 for Mac-1) were activated with phorbol ester (100 nM for LFA-1 and 500 nM for Mac-1) and allowed to react with streptavidin SPA beads previously coated with biotinylated soluble ICAM-1 dispensed into 96 well plates.
  • PBS phosphate buffered saline
  • PBS/HSA human serum albumin
  • JY cells were harvested by centrifugation and fluorescently labeled with 2'7'-bis-(carboxyethyl)-5(6)-carboxy-fluorescien. JY cells were then washed once, in PBS/HSA, and stimulated with phorbol 12-myristate 13-acetate (PMA; 50 ng/ml) for 5 minutes.
  • PMA phorbol 12-myristate 13-acetate
  • microtiter plates was washed once with PBS containing 1 mM Ca 2+ /Mg 2+ and 0.5% Tween-20 and then immediately washed with PBS/HSA.
  • a 80 mL aliquot of cells (1 x 10 5 ) was plated in triplicate on the microtiter wells.
  • a 20 ml aliquot of 5X stock of compound, blocking antibodies or buffer control were added to the wells immediately prior to the addition of cells to the wells.
  • the plates were washed with PBS/HSA. Fluorescence was quantitated in the wells using a Pandex fluorescence concentration analyzer.
  • a secondary adhesion assay using human neutrophils and human soluble ICAM-1 was established.
  • Human neutrophils were used because of the limited availability of cultured cell lines expressing Mac-1.
  • Mac-1 expressed on stimulated neutrophils play a major role in the adherence of neutrophils to endothelial cells and transendothelial migration via its interaction with ICAM-1.
  • Microtiter wells were coated with soluble ICAM-1 diluted in 0.1 mM NaC0 3 buffer (pH 8.0) overnight at 4°C. The remaining binding sites on the plastic were blocked with PBS containing 1 mM Ca 2+ /Mg 2+ and 1% fetal calf serum (PBS/FCS) at room temperature for 30 minutes.
  • PBS/FCS fetal calf serum
  • Neutrophils were purified from the peripheral blood of healthy adult individuals by dextran sedimentation and centrifugation on a Ficoll-Hypaque solution. Neutrophils were then fluorescently labeled with 2'7'-bis-(carboxyethyl)- 5(6)-carboxy-fluorescien. The cells were then washed in PBS/FCS and subjected to hypotonic lysis. To each well, 30 ml of PBS/FCS, 10 ml 10X stock of compound or blocking antibody, 10 ml f-Met-Leu-Phe (10 "7 M), and 50 ml of cells (2 X 10 6 cells/ml) was plated in triplicate. Following incubation for 30 minutes at 37°C, the plates were washed with PBS. Fluorescence was quantitated in the wells using a Pandex fluorescence concentration analyzer.
  • LFA/SPA and Mac-1/SPA refer to LFA-1 and Mac-1 adhesion assays are performed using the SPA technology;
  • JY/ICAM refers to a secondary adhesion assay, inhibition of LFA-1 interactions, using JY and human soluble ICAM-1.
  • PMN/ICAM refers to a secondary adhesion assay, inhibition of Mac-1 interactions, using human neutrophils and human soluble ICAM-1.

Abstract

L'invention concerne un composé de la formule (I) dans lequel R1, R2 et R3 sont tels que définis. Les composés de l'invention sont thérapeutiquement efficaces dans le traitement d'une large gamme de maladies inflammatoires telles que, par exemple, les réactions d'hypersensibilité, l'asthme, la polyarthrite rhumatoïde, la méningite bactérienne, la lésion pulmonaire induite par le syndrome de Mendelson, les troubles intestinaux inflammatoires et complications connexes.
PCT/US1998/021629 1997-10-21 1998-10-20 Amides thiadiazoles utiles comme anti-inflammatoires WO1999020618A1 (fr)

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* Cited by examiner, † Cited by third party
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WO2001027102A1 (fr) * 1999-10-13 2001-04-19 Novartis Ag Diazepans substitues
US6399599B1 (en) 1999-10-13 2002-06-04 Novartis Ag Substituted 2-oxo-1,4-diazacycloalkanes
US6521619B2 (en) 2000-06-29 2003-02-18 Icos Corporation Aryl phenylcyclopropyl sulfide derivatives and their use as cell adhesion inhibiting anti-inflammatory and immune suppressive agents
US6787542B2 (en) 2000-06-29 2004-09-07 Icos Corporation Aryl phenylheterocyclyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents
US6878700B1 (en) 1998-12-29 2005-04-12 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
US6974815B2 (en) 2002-10-11 2005-12-13 Bristol-Myers Squibb Company Hexahydro-benzimidazolone compounds useful as anti-inflammatory agents
USRE39197E1 (en) 1998-12-29 2006-07-18 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
US7186727B2 (en) 2004-12-14 2007-03-06 Bristol-Myers Squibb Company Pyridyl-substituted spiro-hydantoin compounds and use thereof
US7199125B2 (en) 2003-10-02 2007-04-03 Bristol-Myers Squibb Company Spiro-cyclic compounds useful as anti-inflammatory agents
US7375237B2 (en) 2004-08-18 2008-05-20 Bristol-Myers Squibb Company Pyrrolizine compounds useful as anti-inflammatory agents
US7381737B2 (en) 2004-10-01 2008-06-03 Bristol-Myers Squibb Company Crystalline forms and process for preparing spiro-hydantoin compounds
WO2008154563A1 (fr) * 2007-06-11 2008-12-18 Bristol-Myers Squibb Company Activateurs de la glucokinase de type phénylamide à substitution 1,3 hydroxy
CN105837529A (zh) * 2016-04-07 2016-08-10 大连理工大学 一类1,3,4-噻二唑衍生物、制备方法及应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5668159A (en) * 1996-05-08 1997-09-16 The Dupont Merck Pharmaceutical Company 1,3,4-thiadiazoles and 1,3,4-oxadiazoles as IIb/IIIa antagonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5668159A (en) * 1996-05-08 1997-09-16 The Dupont Merck Pharmaceutical Company 1,3,4-thiadiazoles and 1,3,4-oxadiazoles as IIb/IIIa antagonists

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
ACS SYMP. SER., vol. 504, 1992, pages 361 - 70 *
CHEMICAL ABSTRACTS, vol. 118, no. 5, 1 February 1993, Columbus, Ohio, US; abstract no. 34389d, CULLEN TG ET AL: "Nematicidal activity of 5-substituted-2-S-(3,4,4-trifluoro-3- butenyl)-1,3,4-thiadiazoles" page 229; XP002093613 *
CHEMICAL ABSTRACTS, vol. 83, no. 15, 13 October 1975, Columbus, Ohio, US; abstract no. 131514g, SHAMS-EL-DINE SA ET AL: "Chemical studies in the field of oral hypoglycemic agents. III" page 500; XP002093614 *
CHEMICAL ABSTRACTS, vol. 83, no. 25, 22 December 1975, Columbus, Ohio, US; abstract no. 206167g, SHAMS-EL-DINE SA ET AL: "Chemical studies in the field of oral hypoglycemic agents" page 385; XP002093615 *
CROAT. CHEM. ACTA, vol. 33, 1961, pages 121, 123 *
DATABASE CHEMICAL ABSTRACTS ACS; XP002093616 *
DATABASE CHEMICAL ABSTRACTS ACS; XP002093617 *
DATABASE CROSSFIRE Beilstein Institut für Literatur der organischen Chemie; XP002093618 *
DATABASE CROSSFIRE Beistein Institut für Literatur der organischen Chemie; XP002093619 *
FARMACO ED. SCI., vol. 13, 1958, pages 650, 659 *
J. DRUG RES., vol. 6, no. 3, 1974, pages 103 - 8 *
J. DRUG RES., vol. 6, no. 3, 1974, pages 203 - 7 *
KURZER F ET AL: "Heterocyclic compounds from urea derivatives. Part XXI. Adducts from thiocarbonohydrazides and aroyl isothiocyanates and their cyclisation", JOURNAL OF THE CHEMICAL SOCIETY, SECTION C, 1971, pages 2932 - 8, XP002093612 *
OKAWARA T ET AL: "A new route to 1,2,4-triazoles and 1,3,4-thiadiazoles from 1-acylbithiourea", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 25, no. 4, July 1988 (1988-07-01), pages 1071 - 5, XP002093611 *

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