WO1999064418A1 - Aryl-pyridinyl-thiazoles - Google Patents

Aryl-pyridinyl-thiazoles Download PDF

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Publication number
WO1999064418A1
WO1999064418A1 PCT/EP1999/003859 EP9903859W WO9964418A1 WO 1999064418 A1 WO1999064418 A1 WO 1999064418A1 EP 9903859 W EP9903859 W EP 9903859W WO 9964418 A1 WO9964418 A1 WO 9964418A1
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formula
compounds
compound
hydrogen
treatment
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PCT/EP1999/003859
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English (en)
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Richard Heng
Thomas Hugo Keller
Neil John Press
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Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft Mbh
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Priority claimed from GBGB9812117.1A external-priority patent/GB9812117D0/en
Priority claimed from GBGB9818653.9A external-priority patent/GB9818653D0/en
Application filed by Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft Mbh filed Critical Novartis Ag
Priority to AU45063/99A priority Critical patent/AU4506399A/en
Publication of WO1999064418A1 publication Critical patent/WO1999064418A1/fr

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    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • This invention relates to aryl pyridinyl thiazoles, their preparation and their use as pharmaceuticals.
  • the invention provides, in one aspect, a compound which is of formula
  • Ar is an unsubstituted or substituted aryl group linked through an aromatic ring carbon atom thereof to the indicated thiazole ring and R is hydrogen, an acyl group or a monovalent aromatic group having up to 10 carbon atoms linked through an aromatic ring carbon atom to the indicated nitrogen atom, provided that R is not hydrogen when Ar is phenyl or 4-methoxyphenyl.
  • Cj to C 8 alkyl means alkyl having 1 to 8 carbon atoms and is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight or branched pentyl, straight or branched hexyl, straight or branched heptyl or straight or branched octyl. Preferred is to C 4 alkyl.
  • Cj to C 8 alkoxy means alkoxy having 1 to 8 carbon atoms and is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy or straight or branched pentoxy, hexyloxy or octyloxy. Preferred is to C 4 alkoxy.
  • C 5 to cycloalkyl means cycloalkyl having 5 to 8 carbon atoms and is, for example cyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, cycloheptyl and cyclooctyl. Preferred is C ⁇ to C 7 cycloalkyl.
  • "6-membered nitrogen heteroaryl group” means a 6-membered heteroaryl group having one, two or three nitrogen atoms such as pyridinyl (pyridyl), pyrimidinyl or t ⁇ azinyl. Preferred is pyridinyl.
  • the group Ar in formula I may be an aryl group having up to 10 carbon atoms, e.g. phenyl or naphthyl, which may be unsubstituted or substituted, for example by one or more of the substituents hereinafter described.
  • the total number of carbon atoms in Ar, including where present substituents attached to the aromatic ring, may be up to 50, for example up to 33 in preferred compounds and up to 13 in especially preferred compounds of formula III hereinafter described.
  • the group Ar is preferably phenyl which is unsubstituted or substituted by one or more substituents selected from halogen (more preferably chlorine or bromine), Q to C 8 alkyl (more preferably to C 4 alkyl), which is unsubstituted or substituted by halogen, which may be chlorine or, preferably, fluorine, to C 8 alkoxy (more preferably Q to C 4 alkoxy), C 7 to On aralkyloxy (more preferably C 7 to C 9 aralkyloxy), in which the aryl moiety may be unsubstituted or substituted, for example by one or more halogen atoms, C 5 to C 8 cycloalkyl (more preferably to C 7 cycloalkyl), to C 8 alkylamino (more preferably Q to C 4 alkylamino) or di ( -C 8 alkyl)am ⁇ no (more preferably d ⁇ (C]-C 4 alkyl)am ⁇ no).
  • Ar is a group of formula
  • R 1 , R 2 and R 3 are each independently hydrogen, halogen, unsubstituted or halogen- substituted Ci to C 4 alkyl, to C 4 alkoxy, C 7 to C 9 aralkyloxy, C 6 to C 7 cycloalkyl, to C 4 alkylamino or d ⁇ (C ⁇ -C 4 alkyl)am ⁇ no.
  • R 1 , R 2 and R 3 are preferably hydrogen.
  • R 1 is hydrogen, chlorine, bromine, methoxy or methyl
  • R 2 is hydrogen, chlorine, methyl, t ⁇ fluoromethyl, isopropyl, n-butyl, cyclohexyl, methoxy, n-butoxy, benzyloxy or dimethylamino
  • R 3 is hydrogen, methoxy or methyl.
  • R is hydrogen or tnfluoromethyl
  • R 2 is hydrogen, 3,4 dichlorobenzyloxy, 2-phenylethoxy, bromine, 4-methylbenzyloxy, or 4- chlorobenzyloxy
  • R 3 is hydrogen
  • Ar is a group of formula
  • R 1 and R 2 are as hereinbefore defined and R 3 a is Q to C 4 alkyl.
  • An especially preferred group of formula Ha is that in which R is hydrogen, R 2 is chlorine and R 3 a is methyl.
  • the group R in formula I is preferably hydrogen, an acyl group of formula R 4 CO- where R 4 is a Ci to C 4 alkyl group, or in alternative preferred embodiments R is phenyl which is unsubstituted or substituted, preferably by carboxy, or is a 6-membered nitrogen heteroaryl group.
  • R is an acyl group of formula R 4 a CO- where R 4 a is a 5-membered heteroaryl group, preferably furyl.
  • R is acetyl, isobutyryl, carboxyphenyl or pyridinyl.
  • R is propionyl or 3-furoyl.
  • R 1 , R 2 , R 3 and R are as hereinbefore defined, particularly where
  • R 1 and R 2 are chlorine, R is hydrogen and R is hydrogen, acetyl, isobutyryl or 4- carboxyphenyl; or (ii) K 1 and R 3 are hydrogen, R ⁇ is methoxy or methyl and R is hydrogen, acetyl, pyridin-2-yl or pyridin-3-yl; or
  • R 1 is bromine, R 2 is N-dimethylamino, R 3 is hydrogen and R is hydrogen or acetyl; or
  • R 1 and R 3 are methyl, R" is hydrogen and R is hydrogen or acetyl; or
  • R 1 is methyl, R 2 is methyl, R ⁇ is hydrogen and R is hydrogen or acetyl; or
  • R 1 and R 3 are hydrogen, R " is n-butoxy, benzyloxy, n-butyl, isopropyl, trifluoromethyl or cyclohexyl and R is hydrogen or acetyl; or
  • R 1 , R 2 and R 3 are methoxy and R is hydrogen or acetyl.
  • R 1 is methyl, chlorine or trifluoromethyl, R 2 and R 3 are hydrogen and R is hydrogen or acetyl;
  • R 1 is fluorine, R 2 is trifluoromethyl, R 3 is hydrogen and R is hydrogen or acetyl;
  • R 1 is hydrogen, R 2 is chlorine, R 3 is methyl and R is hydrogen or acetyl;
  • R 1 and R 3 are hydrogen, R 2 is 3,4-dichlorobenzyloxy, 2-phenylethoxy, bromine, 4- methylbenzyloxy or 4-chlorobenzyloxy and R is hydrogen or acetyl;
  • R 1 is methyl, chlorine or methoxy, R 2 is benzyloxy, R 3 is hydrogen and R is hydrogen or acetyl;
  • R 1 and R 3 are hydrogen, R " is benzyloxy, and R is 2-pyridinyl, 3-pyridinyl or 3-furoyl;
  • R 1 is methoxy, R 2 is benzyloxy, R 3 is hydrogen and R is propionyl; or
  • R 1 , R 2 and R 3 are each hydrogen.
  • R is hydrogen or acetyl, and pharmaceutically acceptable salts thereof.
  • the compounds represented by the formulae (I) and (III) are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts.
  • Pharmaceutically acceptable acid addition salts of the compound of formula I include those of inorganic acids, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, butyric acid, hydroxy acids such as lactic acid, citric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid.
  • These salts may be prepared from compounds of formula I by known salt-forming procedures.
  • Compounds of formula (I) which contain acidic, e.g. carboxyl, groups, are also capable of forming salts with bases, in particular pharmaceutically acceptable bases such as those well known in the art; suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines, benzylamines or pyridine. These salts may be prepared from compounds of formula I by known salt-forming procedures. These salts may be prepared from compounds of formula I by known salt-forming procedures.
  • halogen preferably bromine
  • R 5 is hydrogen, or a monovalent aromatic group having up to 10 carbon atoms linked through an aromatic ring carbon atom to the indicated nitrogen atom and, where R 5 is hydrogen and a compound of formula I in which R is acyl is desired, reacting the compound obtained with an acylating agent, for example an acid halide or anhydride of a carboxylic acid such as a carboxylic acid of formula R 4 COOH where R 4 is Ci to C 4 alkyl.
  • an acylating agent for example an acid halide or anhydride of a carboxylic acid such as a carboxylic acid of formula R 4 COOH where R 4 is Ci to C 4 alkyl.
  • the reaction of the compound of formula IV with halogen may be carried out using known procedures for the halogenation of ketones, for example in an organic solvent such as dioxane and at a temperature of 10 to 40°C.
  • reaction of the halogenated intermediate with the compound of formula V may be carried out using known procedures for the reaction of alpha-halogenated carbonyl compounds with thioureas to form thiazoles, for example in an organic solvent such as ethanol and at reflux temperature; when R 5 is hydrogen, this reaction results in the formation of a compound of formula I which is also a compound of formula
  • This compound may be reacted with an acylating agent such as hereinbefore described, preferably acetyl chloride, propionyl chloride, isobutyryl chloride or 3-furoyl chloride, using known procedures for the acylation of amines, to give a compound of formula I where R is an acyl group.
  • an acylating agent such as hereinbefore described, preferably acetyl chloride, propionyl chloride, isobutyryl chloride or 3-furoyl chloride, using known procedures for the acylation of amines, to give a compound of formula I where R is an acyl group.
  • Compounds of formula VII may be prepared by reacting a compound of formula Ar-COOH, where Ar is as hereinbefore defined, with dimethylhydroxylamine hydrochloride using known procedures, for example in the presence of NjN'-carbonylbisimidazole at reflux temperature in an organic solvent such as tetrahydrofuran.
  • the invention relates to the use of compounds of formula I and their pharmaceutically acceptable salts, particularly as exemplified herein, as pharmaceuticals.
  • the compounds of formula I and their salts particularly where R is an acyl or monovalent aromatic group, and their salts, exhibit inhibition of human adenosine A3 receptor activation and, moreover, in general selectively inhibit activation of the human adenosine A3 receptor over the Al receptor.
  • Their inhibitory properties relative to the adenosine A3 and Al receptors are demonstrated in the following test procedures:
  • CHO cells lacking a functional gene for dihydrofolate reductase stably transfected with human A3 receptor cDNA are obtained from Research Biology Inc., Baltimore (RBI).
  • the clone is specified by RBI to show >95% specific binding of [ 125 I]-AB MECA, 2000 fmol/mg maximal binding and a Ki value of 0.19nM.
  • the cells are cultivated according to the RBI protocol in sterile IMDM (Iscove's Modified Dulbecco's Medium, Seromed T046-10), supplemented with NaHCO 3 (24mg/l), Penicillin/Streptomycin solution (Seromed A2213) and lOOml/l fetal calf serum (Seromed SOI 15), at 37° C in an atmosphere of 5% CO 2 .
  • cells are trypsinised and split at dilutions below 1:50. Cells are grown to confluence in "Expanded Surface Area" tissue culture flasks (Cellon Sari, Luxemborg, 4450-05), replacing the medium every 3 to 4 days.
  • Membranes are prepared according to the method published by Gallo-Rodriguez et al (J.Med. Chem 1994; 37 : 636-646), omitting incubation with adenosine deaminase.
  • the assay is carried out essentially as described by Gallo-Rodriguez et al in the abovementioned reference.
  • 96-well glass filterplates GF/B, Canberrra Packard
  • 50 ⁇ l/well ethyleneimine polymer Fluka 5mg/ml water, soak time between 10 minutes and 2 hours
  • Assays are carried out in flat- or round-bottomed 96-well microtitre plates in a total volume of 100 ⁇ l (25 ⁇ l of inhibitor solution containing 80 ⁇ l/ml of dimethyl sulfoxide (DMSO), 50 ⁇ l of membranes containing 10 to 25 ⁇ g of protein and 25 ⁇ l of [ 125 I]-AB-MECA (Amersham, 2000Ci/mmol, final concentration 12.5pM, 2.5 nCi/well). After 1 hour of shaking at room temperature, membranes are transferred onto the filterplates using a cell harvester (FilterMate) and washed 5 times.. Plates are dried either overnight or for at least 2 hours at 50° C.
  • DMSO dimethyl sulfoxide
  • Each well receives 40 ⁇ l Microscint 40 (Canberra Packard) and is counted in a scintillation counter (TopCount, Canberra Packard). Nonspecific binding (blanks) is determined in the presence of 10 ⁇ M I-AB-MECA. Control wells receive 25 ⁇ l of 80 ⁇ l/ml DMSO.
  • Inhibition is determined as . 100 /o. control - blank
  • Concentration-inhibition curves are constructed from a series of concentrations consisting of 7 distinct concentrations spanning at least 2 , but usually 3 orders of magnitude. Curves are fitted to the data using the non-linear least squares fitting routines of Microcal Origin 4.1 (Slogistic 1) and results expressed as IC 50 (nM), the concentration of inhibitor at which 50% inhibition is obtained.
  • Incubations are performed in plastic vials, in triplicate, in a final volume of 100 ⁇ l.
  • Membrane bound tracer is separated from free following dilution by 4ml wash buffer (Tris-HCl, 50mM, pH 7.4) followed by rapid filtration through Whatman GF/B glass fibre filters, which have been pre-soaked with polyethyleneimine (0.5% for lh). This is followed by 3 x 3ml washings of the filters. Radioactivity is measured in a scintillation counter. Specific binding of radioligand in the presence of inhibitor (calculated as total binding- non-specific binding) is normalised to the percentage of specific binding in the absence of inhibitor (max binding). IC 50 values (nM) are derived by fitting the results obtained to the Hill equation.
  • the compounds of the Examples hereinbelow which are compounds of formula I where R is an acyl or monovalent aromatic group have IC50 values in the Adenosine A3 assay of the order of from 0.1 to 230 nM, mostly below InM, and have Selectivities (ratios of IC 50 in adenosine A3 assay to IC 50 in Adenosine Al assay) of up to 10,000, mostly greater than 30.
  • the compounds of Examples 9, 10, 11 and 12 have IC 50 values of 0.15nm, 0.23nm, 0.16nm and 0.39nm respectively, and Selectivities of 10,000, 6521, 118 and 3846 respectively
  • Rings are mounted in 20 ml organ baths containing the Krebs bicarbonate solution, gassed with 95% O 2 - 5% CO 2 at 37°C, under a tension of 2g. Isometric changes in tension are recorded. After a 1 hour period, during which the physiological solution is repeatedly renewed and the tension readjusted to 2 g, contraction is induced by repeated (3 times) addition of phenylephrine (3 ⁇ M). After a stable contraction has been reached (60-90 minutes), 5 1 -N-ethylcarboxamidoadenosine (NECA)(adenosine receptor agonist) is added cumulatively in the presence of phenylephrine.
  • NECA 5 1 -N-ethylcarboxamidoadenosine
  • concentration- response curves to NECA are monophasic up to a concentration of lO ⁇ M and are considered to reflect A 2b receptor activation.
  • K B values of the order of from 2nm to l ⁇ M For example, the compounds of Examples 5, 35A and 36A have K B values of 6nm, 5nm, and 2nm respectively.
  • TNF- ⁇ tumour necrosis factor alpha
  • MNC Mononuclear cells
  • the cells are stimulated with lipopolysaccharide (LPS) (l ⁇ g/ml) and IFN- ⁇ (lOng/mL) and supernatants are harvested after 24 hours of incubation at 37°C in a humidified incubator with 5% CO .
  • LPS lipopolysaccharide
  • IFN- ⁇ lOng/mL
  • Concentration of TNF- ⁇ in these supernatants is measured by sandwich ELISA using two monoclonal antibodies recognizing different epitopes of the specific cytokine (mAb357/101-4 and biotinylated 2-179/E11).
  • Optical density is measured at 405 nm and cytokine concentration is calculated based on the results from serial dilutions of standard recombinant human TNF- ⁇ . Values for IC 50 , the concentration of inhibitor at which 50% inhibition of TNF- ⁇ production is obtained, are obtained using the Origin programme.
  • the compounds of formula VI in the Examples hereinbelow have IC 50 values of the order of from 3 to 300nM.
  • Compounds under test are administered either locally by intratracheal instillation as a suspension in saline, or orally by gavage in a vehicle comprising (w/v) 43% Cremophoi RH40, 34% corn oil glycendes, 10% ethanol, 9% propylene glycol and 4% DMSO, 1 hour prior to and 24 hours after antigen exposure.
  • Control groups of actively sensitized animals receive saline alone with or without exposure to antigen.
  • animals are anaesthetised and OA or saline are administered intratracheally, and the animals are killed 24 hours later.
  • compounds under test are administered orally by gavage 1 hour prior to and 6 hours after ovalbumm exposure.
  • Erythrocytes in the BALF are lysed (Quicklyser QLA-200A, TOA Medical Electronics Ltd. Japan). Smears are prepared by diluting the recovered fluid (to approx. 106 cells/mL) and cent ⁇ fuging an aliquot. The smears are air dried, fixed using a solution of fast green in methanol (2 mg/mL) for 5 seconds and stained with eosin G (5 seconds) and thiazin (5 seconds) in order to differentiate cell types. A total of 500 cells per smear are counted by light microscopy under oil immersion (x 1000).
  • Eosinophil peroxidase activity in the lavage fluid is determined by a method based on the oxidation of o-phenylenediamine (OPD) by eosinophil peroxidase in the presence of hydrogen peroxide (H 2 0 2 ).
  • OPD o-phenylenediamine
  • H 2 0 2 hydrogen peroxide
  • the BALF (10 ⁇ L) is mixed with 100 ⁇ L of substrate (1 mM OPD, ImM H 2 O 2 , 0.1 % T ⁇ ton-XlOO, dissolved in 50 mM Tris-HCl pH 8.0) in a 96 well flat bottom microtiter plate and incubated for 30 minutes at room temperature.
  • the reaction is stopped by adding 50 ⁇ l H 2 SO 4 (4M) and absorbance is measured at 492 nm in a microplate absorbance spectrophotometer.
  • concentration of eosinophil peroxidase is calculated as units/ml according to the activity of serial dilutions of a standard horseradish peroxidase (Sigma, 210 U/mg dry wt).
  • Prior administration of compounds of the following Examples reduces eosinophil, neutrophil and total cell count, and reduces eosinophil peroxidase activity compared with untreated controls.
  • the compound of Example 20 administered orally at a dose of 10 mg/kg at -1 hour and +24 hours, shows 70% reduction in eosinophils, 70% reduction in eosinophil peroxidase activity, 70% reduction in neutrophils, and 60% reduction in total cell count, compared with untreated controls; and the compound of Example 1, administered orally at a dose of 10 mg/kg at -1 hour and +6 hours, shows more than 40% reduction in eosinophils and eosinophil peroxidase activity, and about 40% reduction in neutrophils and total cell count, compared with untreated controls.
  • compounds of formula I and their pharmaceutically acceptable salts are indicated for use in the treatment, in particular prophylactic treatment, of obstructive or inflammatory airways disease, e.g. by continued and regular administration over prolonged periods of time, to provide advance protection against recurrence of bronchoconstrictor or other symptomatic attack consequential to obstructive or inflammatory airways disease or to control, ameliorate or reverse basal status of such disease.
  • treatment and “treating” as used throughout the present specification and claims in relation to disease, particularly obstructive or inflammatory airways disease, are to be understood accordingly as embracing both prophylactic and symptomatic modes of therapy.
  • Obstructive or inflammatory airways diseases to which the present invention applies include asthma, pneumoconiosis, chronic obstructive airways or pulmonary disease (COAD or COPD) and adult respiratory distress syndrome (ARDS), as well as exacerbation of airways hyperreactivity consequent to other drug therapy, e.g. aspirin or ⁇ -agonist therapy.
  • COAD or COPD chronic obstructive airways or pulmonary disease
  • ARDS adult respiratory distress syndrome
  • the present invention is applicable to the treatment of asthma of whatever type or genesis, including intrinsic and, especially, extrinsic asthma. It is applicable to the treatment of allergic (atopic/IgE-mediated) asthma. It is also applicable to the treatment of non-atopic asthma, including e.g. bronchitic, exercise induced and occupational asthma, asthma induced following bacterial infection and other non-allergic asthmas. It is further applicable to the treatment of whez infant syndrome (infant, incipient asthma).
  • the invention is applicable to the treatment of pneumoconiosis of whatever type or genesis including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tobaccosis and byssionosis.
  • the invention is applicable to the treatment of COPD or COAD including chronic bronchitis, pulmonary emphysaema or dyspnea associated therewith.
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g. acute, arachidic, catarrhal, chronic, croupus or phthinoid bronchitis.
  • compounds of formula I where R is hydrogen and their pharmaceutically acceptable salts are also indicated for use in the down-regulation or inhibition of TNF- ⁇ release, e.g. for the treatment of diseases or conditions in which TNF- ⁇ release is implicated or plays a mediating role, e.g. diseases or conditions having an aetiology involving or comprising morbid, for example undesirable, excessive or unregulated TNF- ⁇ release, in particular for the treatment of cachexia or endotoxin shock and in treatment of AIDS [cf. Sharief et al, Mediators of inflammation, 1 323-338 (1992)].
  • the invention is applicable to the treatment of cachexia associated with morbid TNF- ⁇ release or TNF- ⁇ blood-serum levels of whatever origin, including cachexia consequential to, e.g. bacterial, viral or parasitic, infection or to deprivation or deterioration of humoral or other organic, e.g. renal function. It is for example applicable to the treatment of cancerous, malarial and vermal cachexia, cachexia resulting from dysfunction of the pituitary, thyroid or thymus glands as well as uremic cachexia. It is in particular applicable to the treatment of AIDS-related cachexia, i.e. cachexia consequential to or associated with HIV infection.
  • compounds of formula I and their pharmaceutically acceptable salts are also indicated for use as immunosuppressive agents, e.g. for the treatment of autoimmune diseases, in particular for the treatment of autoimmune diseases in which inflammatory processes are implicated or which have an inflammatory component or aetiology, or as anti-inflammatory agents for the treatment of inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or aetiology.
  • immunosuppressive agents e.g. for the treatment of autoimmune diseases, in particular for the treatment of autoimmune diseases in which inflammatory processes are implicated or which have an inflammatory component or aetiology
  • anti-inflammatory agents for the treatment of inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or aetiology.
  • diseases to which the present invention is applicable include autoimmune haematological disorders (e.g.
  • haemolytic anaemia haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia
  • systemic lupus erythematosus polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease endocrine opthalmopathy
  • Grave's disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary billiary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, allergic rhinitis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g.
  • idiopathic nephrotic syndrome or minal change nephropathy including idiopathic nephrotic syndrome or minal change nephropathy), as well as inflammatory and/or hyperproliferative skin diseases such as psoriasis, atopic dermatitis, pemphigus and, in particular, contact dermatitis, e.g. allergic contact dermatitis.
  • compounds of formula I and their pharmaceutically acceptable salts are also indicated for use in the treatment of eosinophil related disorders, e.g. eosinophilia, in particular eosinophil related disorders of the airways (e.g.
  • eosinophilic infiltration of pulmonary tissues including hypereosinophilia as it effects the airways and/or lungs as well as, for example, eosinophil- ' related disorders of the airways consequential or concomitant to L ⁇ ffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.
  • hypereosinophilia as it effects the airways and/or lungs as well as, for example, eosinophil- ' related disorders of the airways consequential or concomitant to L ⁇ ffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eos
  • compounds of formula I and their pharmaceutically acceptable salts are also indicated for use as co-therapeutic agents for use in conjunction with such drugs, e.g. as potentiators of therapeutic activity of such drugs or as means of reducing required dosaging or potential side effects of such drugs.
  • drug substances include, e.g. cyclopeptide, cyclopeptolide or macrolide immunosuppressive or anti-inflammatory drug substances, for example drugs belonging to the cyclosporin class, e.g.
  • cyclosporins A or G the drug substances tacrolimus (also known as FK 506), ascomycin and rapamycin and their various known congeners and derivatives, as well as glucocorticosteroid drugs such as budesonide, beclamethasone, fluticasone or mometasone.
  • Diseases to which such co-therapy may be applied include e.g. any disease or condition requiring immunosuppressive or anti- inflammatory drug therapy, e.g. as hereinbefore set forth, in particular for the purposes of immunosuppressive, anti-inflammatory or anti-asthmatic treatment, e.g. to achieve cyclosporin, e.g. cyclosporin A-, macrolide- or steroid-sparing effect.
  • the present invention further provides a compound of formula I or a pharmaceutically acceptable salt thereof as hereinbefore described for use as a pharmaceutical, for example, where R in formula I is an acyl or monovalent aromatic group, for use in the inhibition of adenosine A3 or A2b receptor activation or, where R in formula I is hydrogen, for use in the inhibition of TNF- ⁇ release, and in the treatment of the conditions hereinbefore mentioned, particularly obstructive or inflammatory airways diseases.
  • the present invention also provides a method for the treatment of a condition mediated through release of TNF- ⁇ , in particular an obstructive or inflammatory airways disease, which comprises administering to a subject, particularly a human subject, in need thereof a compound of formula I where R is hydrogen or a pharmaceutically acceptable salt thereof as hereinbefore described.
  • the present invention further provides a method for the treatment of a condition mediated through activation of the adenosine A3 or A2b receptor which comprises administering to a subject, particularly a human subject, in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof as hereinbefore described particularly where R is an acyl group or monovalent aromatic group.
  • the invention provides a method for the treatment of an obstructive or inflammatory airways disease which comprises administering to a subject, particularly a human subject, in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof as hereinbefore described.
  • Dosages employed in practising the present invention will of course vary depending, for example, on the particular condition to be treated, the effect desired and the mode of administration.
  • suitable daily dosages for oral administration are of the order of from 0.2 to 10 mg/kg.
  • the compounds of formula I or their salts may be administered by any appropriate route, e.g. orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, for example in the treatment of asthma; nasally, for example in the treatment of rhinitis; topically to the skin, for example in the treatment of psoriasis; or rectally, for example in the treatment of inflammatory bowel disease.
  • any appropriate route e.g. orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, for example in the treatment of asthma; nasally, for example in the treatment of rhinitis; topically to the skin, for example in the treatment of psoriasis; or rectally, for example in the treatment of inflammatory bowel disease.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier therefor.
  • Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art.
  • oral dosage forms may include tablets and capsules.
  • Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g. patches.
  • Compositions for inhalation may comprise aerosol or other atomizable formulations or dry powder formulations.
  • R 1 , R 2 and R 3 are as shown in the following table
  • R 1 , R 2 and R 3 are as shown in the following table
  • R 1 , R 2 and R 3 are as shown in the following table Compound R 1 R 2 R 3
  • Compound S is 2-pyridylthiourea
  • Compound T is 3-pyridylthiourea
  • Compound U is 4- thioureido-benzoic acid.
  • Example 1 The compound of Example 1 is prepared as follows:
  • 3,4-D ⁇ chlorobenzo ⁇ c acid (25g, 130.88mmol) is dissolved in THF (300ml) under argon and N,N'-carbonylb ⁇ s ⁇ m ⁇ dazole (21.2g, 130.88mmol) is added. The mixture is stirred under reflux for 30m ⁇ ns, then cooled and dimethylhydroxylamine hydrochlo ⁇ de (12.7g, 130.88mmol) is added. The mixture is heated under reflux for 6 hours and then left stirring at room temperature overnight. The solvent is removed and the residue taken up in ether 0.25M HCl. The organic layer is washed a further two times with 0.25M HCl and then three times with aqueous 9% Na 2 CO and brine.
  • Compounds E, J, M, O, ZC, ZF, ZI, ZM and ZP are prepared by procedures analogous to that for Compound B, using Compounds F, K, V, P, ZD, ZG, ZK, ZN and ZQ respectively in place of Compound C. They have the following characteristics:
  • the compounds of Examples 33A to 43A and 46A to 49A are prepared from Examples 33B to 43B and 46B to 49B respectively by a procedure analogous to that of Example 1.
  • the compounds of Examples 44A and 45A are prepared respectively from Examples 44C and 44C hereinafter described by a procedure analogous to that used for the preparation of Compound A.
  • the compounds of Examples 33B to 43B and 46B to 49B are prepared respectively from Examples 33C to 43C and 46C to 49C hereinafter described by a procedure analogous to that used for preparation of Compound A.
  • the compound designated as Example 47B is identical to that designated as Example 46B.
  • the compounds have the following characteristics:
  • Examples 33C to 49C are compounds of formula IX as hereinbefore described where R 3 is hydrogen and R 1 and R 2 are as shown for Examples 33A to 49A respectively in the above table. They are prepared from Examples 33D to 49D respectively hereinafter described by a procedure analogous to that used for the preparation of Compound B. Examples 33D to
  • 49D are compounds of formula X as hereinbefore described where R 3 is hydrogen and R 1 and R 2 are as shown for Examples 33A to 49A respectively in the above table. They are prepared from the corresponding benzoic acid by a procedure analogous to that used for the preparation of compound C.
  • the compounds designated as Examples 44C, 45C and 48C are identical, as are those designated as Examples 44D, 46D and 48D.
  • the compounds have the following characteristics:
  • Example 50A is a compound of formula Ilia as hereinbefore described where R is acetyl; it is prepared from Example 50B by a procedure analogous to that of Example 1.
  • Example 50B is a compound of formula Ilia where R is hydrogen; it is prepared from Example 50C by a procedure analogous to that used for the preparation of Compound A.
  • Example 50C is a compound of formula IV where Ar is a group of formula Ila in which R 1 is hydrogen, R 2 is chlorine and R a is methyl; it is prepared from Example 50D by a procedure analogous to that used for the preparation of Compound B.
  • Example 50D is a compound of formula VII where Ar is as for Example 50C; it is prepared from the corresponding benzoic acid by a procedure analogous to that used for the preparation of Compound C.
  • the compounds have the following characteristics:

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Abstract

La présente invention concerne un composé représenté par la formule générale (I), ou l'un de ses sels. Ar est un groupe aryle substitué ou non substitué où un atome de carbone du cycle aromatique sert de liaison avec le cycle thiazole visé. R est hydrogène, un groupe acyle, ou un groupe aromatique monovalent portant jusqu'à 10 atomes de carbone où un atome de carbone du cycle aromatique sert de liaison avec l'atome d'azote visé. Toutefois, lorsque Ar est phényle ou 4-méthoxyphényle, R n'est pas hydrogène.
PCT/EP1999/003859 1998-06-05 1999-06-03 Aryl-pyridinyl-thiazoles WO1999064418A1 (fr)

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GB9812117.1 1998-06-05
GBGB9812117.1A GB9812117D0 (en) 1998-06-05 1998-06-05 Organic compounds
GB9818653.9 1998-08-26
GBGB9818653.9A GB9818653D0 (en) 1998-08-26 1998-08-26 Organic compounds

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Cited By (25)

* Cited by examiner, † Cited by third party
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WO2001010865A1 (fr) * 1999-08-06 2001-02-15 Takeda Chemical Industries, Ltd. INHIBITEURS DE p38MAP KINASE
WO2001074811A2 (fr) * 2000-03-30 2001-10-11 Takeda Chemical Industries, Ltd. Composes de 1,3-thiazole substitues, production et utilisation desdits composes
WO2002042298A1 (fr) * 2000-11-21 2002-05-30 Novartis Ag Aminothiazoles et utilisation de ceux-ci comme antagonistes du recepteur de l'adenosine
EP1283056A1 (fr) * 2000-04-26 2003-02-12 Eisai Co., Ltd. Compositions medicinales favorisant les mouvements intestinaux
WO2003015773A2 (fr) 2001-08-13 2003-02-27 Janssen Pharmaceutica N.V. Derives de thiazolyl 2-amino-4,5-trisubstitue
JP2003512467A (ja) * 1999-10-27 2003-04-02 ノバルティス アクチエンゲゼルシャフト チアゾールおよびイミダゾ（４，５−ｂ）ピリジン化合物ならびにそれらの医薬用途
WO2003039451A2 (fr) * 2001-11-08 2003-05-15 Fujisawa Pharmaceutical Co., Ltd. Derive de thiazole et utilisation pharmaceutique
US6586423B2 (en) 1999-09-10 2003-07-01 Merck & Co., Inc. Tyrosine kinase inhibitors
EP1364949A1 (fr) * 2001-02-02 2003-11-26 Takeda Chemical Industries, Ltd. Inhibiteur de jnk
EP1390068A1 (fr) * 2001-05-18 2004-02-25 Endacea, Inc. Methodes et formules d'utilisation d'antagonistes des purinorecepteurs de l'adenosine a 1 et de p 2x
US6872724B2 (en) 2002-07-24 2005-03-29 Merck & Co., Inc. Polymorphs with tyrosine kinase activity
US6875767B2 (en) 2001-06-22 2005-04-05 Merck & Co., Inc. (5-cyano-2-thiazolyl)amino-4-pyridine tyrosine kinase inhibitors
WO2005070926A1 (fr) * 2004-01-21 2005-08-04 Novartis Ag Derives de thiazole en tant qu'antagonistes de a2b
WO2006032273A1 (fr) * 2004-09-22 2006-03-30 H. Lundbeck A/S Derives de 2-acylaminothiazole
US7105550B2 (en) 2000-03-01 2006-09-12 Christopher Love 2,4-disubstituted thiazolyl derivatives
WO2006137527A1 (fr) 2005-06-23 2006-12-28 Kyowa Hakko Kogyo Co., Ltd. Dérivé du thiazole
US7160892B2 (en) 2001-10-22 2007-01-09 Eisai Co., Ltd. Pyrimidone compounds and pharmaceutical compositions containing the same
WO2007015528A1 (fr) 2005-08-02 2007-02-08 Kyowa Hakko Kogyo Co., Ltd. Agent de traitement et/ou de prevention des troubles du sommeil
JP2008513385A (ja) * 2004-09-22 2008-05-01 ハー・ルンドベック・アクチエゼルスカベット ２−アシルアミノチアゾール誘導体
US7674912B2 (en) 2005-04-25 2010-03-09 H. Lundbeck A/S Pro-drugs of N-thiazol-2-yl-benzamide derivatives
US7718808B2 (en) 2003-12-26 2010-05-18 Kyowa Hakko Kirin Co., Ltd. Thiazole derivatives
EP2198710A1 (fr) 2008-12-19 2010-06-23 Bayer CropScience AG Utilisation de 5-pyridine-4yl-(1,3)thiazoles destinés à lutter contre les champignons phytopathogènes
WO2016116652A1 (fr) 2015-01-22 2016-07-28 Palobiofarma, S.L. Modulateurs des récepteurs d'adénosine a3
WO2018134464A1 (fr) 2017-01-20 2018-07-26 Palobiofarma, S.L. Modulateurs des récepteurs a3 de l'adénosine
CN109293652A (zh) * 2017-07-24 2019-02-01 四川科伦博泰生物医药股份有限公司 一种取代的噻唑衍生物及其用途

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EP0308020A2 (fr) * 1987-09-18 1989-03-22 Merck & Co. Inc. Les acides 5-(aryl et hétéroaryl)-6-(aryl et hétéroaryl)-1,2-dihydro-2-oxo-3-pyridinecarboxyliques et leurs dérivés
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WO2001010865A1 (fr) * 1999-08-06 2001-02-15 Takeda Chemical Industries, Ltd. INHIBITEURS DE p38MAP KINASE
US6962933B1 (en) 1999-08-06 2005-11-08 Takeda Pharmaceutical Company Limited Method for inhibiting p38 MAP kinase or TNF-α production using a 1,3-thiazole
US6586423B2 (en) 1999-09-10 2003-07-01 Merck & Co., Inc. Tyrosine kinase inhibitors
US6586424B2 (en) 1999-09-10 2003-07-01 Merck & Co., Inc. Tyrosine kinase inhibitors
JP2003512467A (ja) * 1999-10-27 2003-04-02 ノバルティス アクチエンゲゼルシャフト チアゾールおよびイミダゾ（４，５−ｂ）ピリジン化合物ならびにそれらの医薬用途
US7105550B2 (en) 2000-03-01 2006-09-12 Christopher Love 2,4-disubstituted thiazolyl derivatives
US7893280B2 (en) 2000-03-01 2011-02-22 Janssen Pharmaceutica Nv 2,4-disubstituted thiazolyl derivatives
WO2001074811A2 (fr) * 2000-03-30 2001-10-11 Takeda Chemical Industries, Ltd. Composes de 1,3-thiazole substitues, production et utilisation desdits composes
WO2001074811A3 (fr) * 2000-03-30 2002-02-07 Takeda Chemical Industries Ltd Composes de 1,3-thiazole substitues, production et utilisation desdits composes
US7495018B2 (en) 2000-03-30 2009-02-24 Takeda Pharmaceutical Company Limited Substituted 1,3-thiazole compounds, their production and use
EP1283056A1 (fr) * 2000-04-26 2003-02-12 Eisai Co., Ltd. Compositions medicinales favorisant les mouvements intestinaux
KR100782091B1 (ko) * 2000-04-26 2007-12-04 에자이 알앤드디 매니지먼트 가부시키가이샤 배변을 촉진하는 의약 조성물
EP1283056A4 (fr) * 2000-04-26 2003-07-02 Eisai Co Ltd Compositions medicinales favorisant les mouvements intestinaux
US7189717B2 (en) 2000-04-26 2007-03-13 Eisai Co., Ltd. Medicinal compositions promoting bowel movement
US7109202B2 (en) 2000-11-21 2006-09-19 Novartis Ag Aminothaizoles and their use as adenosine receptor antagonists
WO2002042298A1 (fr) * 2000-11-21 2002-05-30 Novartis Ag Aminothiazoles et utilisation de ceux-ci comme antagonistes du recepteur de l'adenosine
EP1364949A1 (fr) * 2001-02-02 2003-11-26 Takeda Chemical Industries, Ltd. Inhibiteur de jnk
US7199124B2 (en) 2001-02-02 2007-04-03 Takeda Pharmaceutical Company Limited JNK inhibitor
EP1364949A4 (fr) * 2001-02-02 2005-11-23 Takeda Pharmaceutical Inhibiteur de jnk
EP1390068A1 (fr) * 2001-05-18 2004-02-25 Endacea, Inc. Methodes et formules d'utilisation d'antagonistes des purinorecepteurs de l'adenosine a 1 et de p 2x
EP1390068A4 (fr) * 2001-05-18 2006-04-05 Endacea Inc Methodes et formules d'utilisation d'antagonistes des purinorecepteurs de l'adenosine a 1 et de p 2x
US6875767B2 (en) 2001-06-22 2005-04-05 Merck & Co., Inc. (5-cyano-2-thiazolyl)amino-4-pyridine tyrosine kinase inhibitors
US7803823B2 (en) 2001-08-13 2010-09-28 Janssen Pharmaceutica Nv 2-amino-4,5-trisubstituted thiazolyl derivatives
WO2003015773A2 (fr) 2001-08-13 2003-02-27 Janssen Pharmaceutica N.V. Derives de thiazolyl 2-amino-4,5-trisubstitue
US7232838B2 (en) 2001-08-13 2007-06-19 Janssen Pharmaceutica N.V. 2-amino-4,5-trisubstituted thiazolyl derivatives
US7160892B2 (en) 2001-10-22 2007-01-09 Eisai Co., Ltd. Pyrimidone compounds and pharmaceutical compositions containing the same
WO2003039451A3 (fr) * 2001-11-08 2003-09-25 Fujisawa Pharmaceutical Co Derive de thiazole et utilisation pharmaceutique
WO2003039451A2 (fr) * 2001-11-08 2003-05-15 Fujisawa Pharmaceutical Co., Ltd. Derive de thiazole et utilisation pharmaceutique
US6872724B2 (en) 2002-07-24 2005-03-29 Merck & Co., Inc. Polymorphs with tyrosine kinase activity
US7718808B2 (en) 2003-12-26 2010-05-18 Kyowa Hakko Kirin Co., Ltd. Thiazole derivatives
EP3002283A1 (fr) 2003-12-26 2016-04-06 Kyowa Hakko Kirin Co., Ltd. Dérivés de thiazole
US8889718B2 (en) 2003-12-26 2014-11-18 Kyowa Hakko Kirin Co., Ltd. Thiazole derivatives
US8420827B2 (en) 2003-12-26 2013-04-16 Kyowa Hakko Kirin Co., Ltd. Thiazole derivatives
US7880013B2 (en) 2003-12-26 2011-02-01 Kyowa Hakko Kirin Co., Ltd. Thiazole derivatives
WO2005070926A1 (fr) * 2004-01-21 2005-08-04 Novartis Ag Derives de thiazole en tant qu'antagonistes de a2b
CN1910178B (zh) * 2004-01-21 2010-06-02 诺瓦提斯公司 作为a2b拮抗剂的噻唑衍生物
US7910613B2 (en) 2004-09-22 2011-03-22 H. Lundbeck A/S 2-acylaminothiazole derivatives
WO2006032273A1 (fr) * 2004-09-22 2006-03-30 H. Lundbeck A/S Derives de 2-acylaminothiazole
JP2008513385A (ja) * 2004-09-22 2008-05-01 ハー・ルンドベック・アクチエゼルスカベット ２−アシルアミノチアゾール誘導体
JP4942045B2 (ja) * 2004-09-22 2012-05-30 ハー・ルンドベック・アクチエゼルスカベット ２−アシルアミノチアゾール誘導体
US7674912B2 (en) 2005-04-25 2010-03-09 H. Lundbeck A/S Pro-drugs of N-thiazol-2-yl-benzamide derivatives
WO2006137527A1 (fr) 2005-06-23 2006-12-28 Kyowa Hakko Kogyo Co., Ltd. Dérivé du thiazole
US7928098B2 (en) 2005-08-02 2011-04-19 Kyowa Hakko Kirin Co., Ltd. Therapeutic and/or preventive agents for a sleep disorder
WO2007015528A1 (fr) 2005-08-02 2007-02-08 Kyowa Hakko Kogyo Co., Ltd. Agent de traitement et/ou de prevention des troubles du sommeil
US9198426B2 (en) 2008-12-19 2015-12-01 Bayer Intellectual Property Gmbh Use of 5 pyridin-4-yl-1,3-thiazoles for controlling phytopathogenic fungi
EP2198710A1 (fr) 2008-12-19 2010-06-23 Bayer CropScience AG Utilisation de 5-pyridine-4yl-(1,3)thiazoles destinés à lutter contre les champignons phytopathogènes
WO2016116652A1 (fr) 2015-01-22 2016-07-28 Palobiofarma, S.L. Modulateurs des récepteurs d'adénosine a3
US10238637B2 (en) 2015-01-22 2019-03-26 Palobiofarma, S.L. Modulators of the adenosine A3 receptors
WO2018134464A1 (fr) 2017-01-20 2018-07-26 Palobiofarma, S.L. Modulateurs des récepteurs a3 de l'adénosine
JP2020505349A (ja) * 2017-01-20 2020-02-20 パロビオファルマ、ソシエダッド、リミターダＰａｌｏｂｉｏｆａｒｍａ Ｓ．Ｌ アデノシンａ３受容体の調節剤
EA038011B1 (ru) * 2017-01-20 2021-06-22 Палобиофарма, С.Л. Модуляторы аденозиновых рецепторов a3
CN109293652B (zh) * 2017-07-24 2021-10-22 四川科伦博泰生物医药股份有限公司 一种取代的噻唑衍生物及其用途
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