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    • 专利摘要:
    The present invention provides compounds of formula I in free or salt form. Wherein Ar is a monovalent aromatic group of C 6 -C 15 , R 1 is hydrogen, halogen, cyano, hydroxy, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 1 -C Phenyl optionally substituted with one or more substituents selected from 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl or acyloxy, or a 5- or 6-membered monovalent heterocyclic group, R 2 is hydrogen, C 1 -C 8 -alkyl, acyl or -CON (R 3 ) R 4 , provided that when R 1 is hydrogen, R 2 is C 1 -C 8 -alkyl, acyl or -CON (R 3 R 4 , R 3 and R 4 each independently represent a hydrogen or C 1 -C 8 -alkyl, or a 5- or 6-membered heterocyclic group together with the nitrogen atom to which they are attached, Z 1 , Z 2 , Z 3 and Z 4 are each independently N or CR 5 , at least one of them is CR 5 , and R 5 is hydrogen, C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy.
    公开号:KR20040007412A
    申请号:KR10-2003-7006156
    申请日:2001-11-19
    公开日:2004-01-24
    发明作者:프레스네일존；태일러로저존
    申请人:노파르티스 아게；
    IPC主号:
    专利说明:

    Aminothiazoles and their use as adenosine receptor antagonists
    [1] The present invention relates to organic compounds, their preparation and their use as medicaments.
    [2] In one aspect, the present invention provides a compound of formula I in free or salt form.
    [3]
    [4] Wherein Ar is a monovalent aromatic group of C 6 -C 15 ,
    [5] R 1 is hydrogen, halogen, cyano, hydroxy, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C Phenyl optionally substituted with one or more substituents selected from 8 -alkyl or acyloxy, or a 5- or 6-membered monovalent heterocyclic group,
    [6] R 2 is hydrogen, C 1 -C 8 -alkyl, acyl or -CON (R 3 ) R 4 , provided that when R 1 is hydrogen, R 2 is C 1 -C 8 -alkyl, acyl or -CON (R 3 ) R 4 ,
    [7] R 3 and R 4 each independently represent hydrogen or C 1 -C 8 -alkyl, or a 5- or 6-membered heterocyclic group together with the nitrogen atom to which they are attached,
    [8] Z 1 , Z 2 , Z 3 and Z 4 are each independently N or CR 5 , at least one of them is CR 5 ,
    [9] R 5 is hydrogen, C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy.
    [10] The terms used herein have the following meanings:
    [11] C 1 -C 8 -alkyl as used herein refers to straight or branched C 1 -C 8 -alkyl, 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. Preferably C 1 -C 8 -alkyl is C 1 -C 4 -alkyl.
    [12] As used herein, C 1 -C 8 -alkoxy refers to straight or branched C 1 -C 8 -alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butuxi, isobutane Tux, sec-butux, tert-butuxi, straight or branched pentoxy, straight or branched hexyloxy, straight or branched heptyloxy, or straight or branched octyloxy. Preferably C 1 -C 8 -alkoxy is C 1 -C 4 -alkoxy.
    [13] C 1 -C 8 -haloalkyl as used herein denotes C 1 -C 8 -alkyl as described above substituted by one or more halogen atoms, preferably 1, 2 or 3 halogen atoms, preferably fluorine Or a chlorine atom. Preferably C 1 -C 8 -haloalkyl is C 1 -C 4 -alkyl substituted with 1, 2 or 3 fluorine or chlorine atoms.
    [14] C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl as used herein denotes C 1 -C 8 -alkyl as described above substituted by C 1 -C 8 -alkoxy.
    [15] C 1 -C 8 -alkoxy-C 1 -C 8 -alkoxy, as used herein, refers to C 1 -C 8 -alkoxy, substituted above by C 1 -C 8 -alkoxy.
    [16] A C 1 -C 8 used in this specification - alkylcarbonyl, C 1 -C 8 - haloalkyl carbonyl and C 1 -C 8 - alkoxycarbonyl nilneun carbon atom a carbonyl group, the aforementioned each of the C 1 attached to the - C 8 -alkyl, C 1 -C 8 -haloalkyl or C 1 -C 8 -alkoxy.
    [17] Acyl as used herein refers to alkylcarbonyl, for example C 1 -C 8 -alkylcarbonyl (C 1 -C 8 -alkyl can be one C 1 -C 8 -alkyl group described above, optionally one May be substituted with one or more halogen atoms); Cycloalkylcarbonyl, such as C 3 -C 8 -cycloalkylcarbonyl, wherein C 3 -C 8 -cycloalkyl can be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl ); 5- or 6-membered heterocyclylcarbonyl, such as furylcarbonyl, methylthienylcarbonyl or pyridyl, having one or more, preferably one or two, heteroatoms selected from nitrogen, oxygen and sulfur in the ring Carbonyl; Arylcarbonyls such as C 6 -C 10 -arylcarbonyl such as benzoyl; Or C 6 -C 10 -aryl-C 1 -C 4 -alkylcarbonyl, such as aralkylcarbonyl, such as benzylcarbonyl or phenylethylcarbonyl.
    [18] Acyloxy as used herein may be alkylcarbonyloxy, such as C 1 -C 8 -alkylcarbonyloxy, wherein C 1 -C 8 -alkyl may be one C 1 -C 8 -alkyl group described above Optionally optionally substituted with one or more halogen atoms); Cycloalkylcarbonyloxy, such as C 3 -C 8 -cycloalkylcarbonyloxy, wherein C 3 -C 8 -cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctylyl Can be); 5- or 6-membered heterocyclylcarbonyloxy having 1 or 2 hetero atoms selected from nitrogen, oxygen and sulfur in the ring such as furylcarbonyloxy or pyridylcarbonyloxy; Arylcarbonyloxy such as C 6 -C 10 -arylcarbonyloxy such as benzoyloxy; Or C 6 -C 10 -aryl-C 1 -C 4 -alkylcarbonyloxy, such as aralkylcarbonyloxy, such as benzylcarbonyloxy or phenylethylcarbonyloxy. Preferably acyloxy is C 1 -C 4 -alkylcarbonyloxy.
    [19] Halogen as used herein may be fluorine, chlorine, bromine or iodine; Preferably fluorine or chlorine.
    [20] Ar may be, for example, phenyl optionally substituted by one, two or three substituents selected from one or more substituents, such as halogen, cyano, C 1 -C 8 -alkyl or C 1 -C 8 -haloalkyl, or , Ar may be naphthyl. Ar may preferably be phenyl optionally substituted by halogen, cyano or C 1 -C 8 -alkyl, preferably in the meta or para position relative to the thiazole ring.
    [21] R 1 is, for example, hydrogen, halogen, cyano, hydroxy, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, carboxy, C 1 -C 8 -alkoxycarbonyl or C 1 -C 8 -alkylcarbonyloxy or 1 having 1, 2 or 3 ring heteroatoms selected from nitrogen, oxygen and sulfur May be phenyl optionally substituted by a 5- or 6-membered heterocyclic group, for example C 1 -C 8 -alkyl, hydroxy, C 1 -C 8 -alkoxy or C 1 -C 8 -alkoxy- Pyrrolyl, triazolyl, pyridyl, oxopyridyl, piperidyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyra optionally substituted by one or more substituents selected from C 1 -C 8 -alkoxy Zolinyl, piperazinyl, morpholinyl, furyl, pyranyl, thienyl or thiazolyl. Preferably R 1 is phenyl optionally substituted by hydrogen, cyano or C 1 -C 4 -alkoxy, or a monovalent 6-membered N-heterocyclic group, preferably a heteroaromatic group, in particular pyridyl, C 1 -C 4 -alkylpyridyl, di (C 1 -C 4 -alkyl) pyridyl, C 1 -C 4 -alkoxypyridyl, pyrazinyl, C 1 -C 4 -alkylpyrazinyl, C 1 -C 4 -Alkoxypyrazinyl or C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxypyrazinyl.
    [22] R 2 is, for example, hydrogen, C 1 -C 8 - alkyl, formyl, C 1 -C 8 - alkylcarbonyl, C 1 -C 8 - haloalkyl-carbonyl, C 3 -C 8 - cycloalkyl-carbonyl, phenyl Carbonyl, wherein the phenyl moiety is optionally substituted with halogen, cyano, hydroxy, C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy, heterocyclylcarbonyl, wherein the heterocyclyl group is 5- or 6-membered, having at least one, preferably nitrogen, oxygen and sulfur, or 1 or 2 ring heteroatoms selected from the group -CON (R 3 ) R 4 ). Preferably R 2 is hydrogen, C 1 -C 4 -alkylcarbonyl, C 3 -C 6 -cycloalkylcarbonyl, phenylcarbonyl, wherein the phenyl group is optionally substituted by C 1 -C 8 -alkoxy ), Or heterocyclylcarbonyl, wherein the heterocyclyl group is 5- or 6-membered and has a ring hetero atom selected from nitrogen, oxygen and sulfur, such as furylcarbonyl, tetrahydrofurylcarbonyl , C 1 -C 4 -alkylfurylcarbonyl, thienylcarbonyl, C 1 -C 4 -alkyl-thienylcarbonyl, N- (C 1 -C 4 -alkyl) pyrrolylcarbonyl and pyridylcarbonylyl Can be.
    [23] R 3 and R 4 , if present, each independently represent, for example, hydrogen or C 1 -C 4 -alkyl, or a 5-membered heterocyclyl group such as pyrrolyl or pyrrolidinyl together with the nitrogen atom to which they are attached or 6-membered heterocyclyl group such as pyridyl, piperidyl, piperazinyl or morpholinyl. Preferably, R 3 and R 4 , if present, may represent C 1 -C 8 -alkyl, in particular methyl, or 5- or 6-membered heterocyclyl groups, in particular pyridyl, together with the nitrogen atom to which they are attached have.
    [24] When there are two or more Z 1, Z 2, Z 3 and Z 4 represent a CR 5, CR 5 groups may be the same or different. Preferably R 5 is hydrogen or C 1 -C 4 -alkyl. Preferably, Z 1 and Z 3 each represent N, Z 2 and Z 4 each independently represent CR 5 , or Z 2 represents N, and Z 1 , Z 3 and Z 4 are each independently CR 5 Wherein R 5 is hydrogen or C 1 -C 4 -alkyl. In a particularly preferred embodiment, Z 1 and Z 3 each represent N and Z 2 and Z 4 each represent CH or Z 1 represents CR 5 , wherein R 5 represents hydrogen or C 1 -C 4- Alkyl, Z 2 represents N, and Z 3 and Z 4 each represent CH.
    [25] Preferred compounds of formula (I) in free or salt form are:
    [26] Ar is phenyl optionally substituted by halogen or cyano,
    [27] R 1 is hydrogen, cyano or phenyl optionally substituted by C 1 -C 4 -alkoxy, or a monovalent 6-membered N-heterocyclic group,
    [28] R 2 is hydrogen, C 1 -C 4 -alkylcarbonyl, C 3 -C 6 -cycloalkylcarbonyl, phenylcarbonyl, wherein the phenyl group is optionally substituted by C 1 -C 4 -alkoxy, or Heterocyclylcarbonyl, wherein the heterocyclyl group is 5- or 6-membered and has 1 or 2 ring heteroatoms selected from nitrogen, oxygen and sulfur, and Z 1 and Z 3 are each N Z 2 and Z 4 each represent CH, or Z 1 represents CR 5 (wherein R 5 is hydrogen or C 1 -C 4 -alkyl), Z 2 represents N, Z 3 and Z 4 represents CH, respectively.
    [29] More preferred compounds of formula I in free or salt form are as follows:
    [30] Ar is phenyl in which the meta or para position is substituted with halogen or cyano for the thiazole ring,
    [31] R 1 is a monovalent 6-membered N-heterocyclic group,
    [32] R 2 is hydrogen,
    [33] Z 1 and Z 3 each represent N, Z 2 and Z 4 each represent CH, or Z 1 represents CR 5 , wherein R 5 is hydrogen or C 1 -C 4 -alkyl, Z 2 Represents N, and Z 3 and Z 4 each represent CH.
    [34] Other more preferred free or salt forms of the compound of formula I are as follows:
    [35] Ar is phenyl substituted by halogen or cyano in the meta or para position with respect to the thiazole ring,
    [36] R 1 is hydrogen,
    [37] R 2 is phenylcarbonyl, wherein phenyl is optionally substituted by C 1 -C 4 -alkoxy, or heterocyclylcarbonyl, wherein the heterocyclyl group is 5- or 6-membered, oxygen and sulfur Z 1 and Z 3 each represent N, Z 2 and Z 4 each represent CH, or Z 1 represents CR 5 , wherein R 5 represents hydrogen or C 1 -C 4 -alkyl, Z 2 represents N, and Z 3 and Z 4 each represent CH.
    [38] Particularly preferred compounds of formula I are described below in the Examples.
    [39] The compounds represented by the formula (I) can form acid addition salts, in particular pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable acid addition salts of compounds of formula (I) include inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; And aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, benzoic acid, p-chlorobenzoic acid, diphenyl Aromatic carboxylic acids such as acetic acid or tridiphenylacetic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, aromatic hydroxy acids such as 1-hydroxynaphthalene-2-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid and methane Salts with organic acids such as sulfonic acids such as sulfonic acids or benzenesulfonic acids.
    [40] Compounds of formula (I) which contain acids, such as carboxyl groups, may also form salts with bases, especially pharmaceutically acceptable bases such as, for example, known bases; Suitable salts such as salts including metal salts, in particular alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, salts with ammonia or pharmaceutically acceptable organic amines or ethanolamines, benzylamines or pyridine The same heterocyclic base cyclic base can be used. The salts can be prepared from compounds of formula (I) by known salting methods.
    [41] In another aspect, the invention provides a process for the preparation of a compound of formula (I) in free or salt form, including:
    [42] (i) (A) For the preparation of compounds of formula I, wherein R 1 is optionally substituted with phenyl or a 5- or 6-membered heterocyclic group, the salts of the following formulas of the Compounds of II wherein X is halogen, preferably bromine or iodine, are compounds of Formula III wherein R 1 is halogen, cyano, hydroxy, C 1 -C 8 -alkyl, C 1 -C Phenyl optionally substituted with one or more substituents selected from 8 -haloalkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl and acyloxy, or R 1 is 5- or A 6-membered monovalent heterocyclic group, R 2 is H or C 1 -C 8 -alkyl, or
    [43]
    [44]
    [45] (B) For the preparation of compounds of formula (I) wherein R 1 is optionally substituted with phenyl or a 5- or 6-membered heterocyclic group, the compounds of formula (IV) (Ar, R 1 , R 2 and X is as described above) or a compound of formula (V)
    [46]
    [47]
    [48] (C) a compound of formula (VI), wherein R 1 is as defined above in formula (I) to prepare a compound of formula (I) wherein R 2 is acyl or -CON (R 3 ) R 4 ) Is reacted with an acylated derivative of carboxylic acid, such as anhydride or acid halide thereof or a compound of formula Cl-CON (R 3 ) R 4 ), respectively,
    [49]
    [50] Here, Ar, Z 1 , Z 2 , Z 3 , Z 4 , R 3 , R 4 are as described above.
    [51] (ii) recovery of the compound of formula (I) in the form of the free or salt produced.
    [52] Alternative (A) can be carried out in an organic solvent such as an alcohol such as ethanol or a tertiary base such as pyridine. Suitable reaction temperatures are the reflux temperature of the solvent at elevated temperatures, such as 50 ° C.
    [53] Alternative (B) can be carried out by known methods, for example by heating the reaction in an inert solvent. Suitable reaction temperatures are, for example, 160 ° C. at 80 ° C.
    [54] Alternative (C) can be carried out using known methods for reacting amines with acylating agents.
    [55] Compounds of formula II can be prepared by reacting a compound of formula VII with halogen X 2 , preferably bromine:
    [56]
    [57] Here, Ar, Z 1 , Z 2 , Z 3 and Z 4 are as described above. The halogenation can be carried out using a known method for alpha halogenation such as ketones. For example, it is described in the following examples. The reaction can be carried out in situ in the presence of a compound of formula III to which a compound of formula II is reacted to form a compound of formula I.
    [58] Compounds of formula III are thiouria obtainable by known or known methods. For example, a compound of formula VIII, wherein R 1 and R 2 are defined as above, is reacted with benzoyl isothiocyanate and the resulting product is hydrolyzed to form a benzoyl group, for example, using aqueous NaOH. Substituted by halogen group. The reaction with benzoyl isothiocyanate can be carried out in an organic solvent such as an alcohol such as ethanol. Suitable reaction temperatures are between room temperature and the reflux temperature of the solvent, conveniently 35-45 ° C. Hydrolysis can be carried out at elevated temperatures, eg at reflux at 70 ° C., at reflux.
    [59]
    [60] The compound of formula IV is formula (III) using compounds of formula (IX) wherein Ar and X are defined as above, for example, using known methods such as those described in the reaction of compounds of formulas (II) and (III) And the resulting aminothiazole can be prepared by brominating, such as known methods or alternatives thereof, such as the methods of the following examples.
    [61]
    [62] Compounds of formula V are known commercially available compounds or may be prepared by known methods. Compounds of formula (VI) can be prepared by the alternatives (A) or (B) described above. Compounds of formula (VII) can be prepared by using compounds of formula (IX) with sodium derivatives of compounds of formula (V), for example by the known methods described in the Examples below. Compounds of formulas VIII and IX can be obtained by known methods, such as those known or described in the Examples below.
    [63] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments. In particular they are inhibitors of adenosine A2b receptor activity, in particular, they are A2b receptor antagonists. In general they also selectively inhibit the activity of A2b receptors on adenosine A1 and A2a receptors. Their inhibitory properties can be demonstrated in the following experimental methods.
    [64] Adenosine A2b Receptor Reporter Gene Assays
    [65] a) Culture of Chinese Hamster Ovary (CHO) A2b cell line
    [66] 10% v / v Fetal Bovine Serum (FCS), 2 mM L-glutamine, 0.4 mg 37 ° C., 5% CO in Dulbecco's Modified Eagle Medium (DMEM) with / ml L-Proline, 1 nM sodium selenite, 0.5 mg / ml Hygromycin B and 1 mg / ml Geneticin Incubated routinely at 2 and 100% humidity. The obtained cells were passaged using trypsin / EDTA and expanded at a ratio of 1 in 5.
    [67] b) preparation of cells for assays
    [68] Prior to assay, CHO-A2b cells were applied onto a white 96-well view plate tissue culture plate (Packard) at a concentration of 50,000 cells per well in 50 μl of DMEM, and the plate was 37 ° C., 5% CO 2 and 100% humidity. Incubated at.
    [69] c) comparison and preparation of test compounds
    [70] A 10 mM solution of comparative compound, xanthine amine Cogener (XAC) and dimethyl sulfoxide (DMSO) was prepared. The solution was further diluted with DMSO to 100 μM, then diluted to 10 μM, and finally assay buffer (DMEM phenol added with 10 μM Rolipram and 10 U / ml adenosine deaminase (ADA)). Diluted to 250 nM or 2.5 μM in retro-tissue tissue culture medium The resulting solution (40 μl) was added to cells on a suitable well, the final concentration per well was 100 nM or 1 μM and the plate was 37 ° C., 5% CO 2. And 100% humidity.
    [71] d) Luciferase reporter gene assay
    [72] 5'-N-ethylcarboxamidoadenosine (NECA), adenosine A2b agonist was prepared as a 10 nM solution in DMSO and then diluted to 100 μM with assay buffer. The solutions were serially diluted in assay buffer to prepare a series of 10 NECA concentrations at concentrations of 100-0.01 μM. A 10 μl portion of the resulting NECA solution was added to the CHO-A2b cells prepared above and the comparative or test compound solution (preincubated for 30 minutes) and the final concentration was in the range of 10-0.0005 μM per well. Cells are then incubated at 37 ° C., 5% CO 2, and 100% humidity for 3 hours to induce the secretion of cAMP that binds to cAMP binding protein (CBP), and the resulting complex is combined with a reporter plasmid to express luciferase. Reacted. 100 μl of Luciferase Assay substrate from Steady-Glo, Promega was added to all wells to lyse and generate fluorescence in proportion to the amount of luciferase produced. Plates were left for a minimum of 5 minutes before reading on a fluorescence program on a Topcount NXT microplate scintillation counter (ex Packard). Concentration dependent curves were plotted from fluorescence data using Activitybase software, and K B values for antagonists were calculated from the shifts of the curve at specific concentrations (K B = [antagonist] / (concentration ratio −1)
    [73] The compounds of the following examples have K B values of 300 nM or less in the reporter gene assay. For example, the compounds of Examples 12, 15, 16, 17, 27, 35, 36 and 38 have K B values of 31 nM, 20 nM, 24 nM, 26.5 nM, 10 nM, 4 nM, 17 nM and 12 nM, respectively.
    [74] In general, compounds of formula (I) in free or pharmaceutically acceptable salt form also exhibit inhibition of adenosine A3 receptor activity, which can be demonstrated in the adenosine A3 receptor assays described in WO 99/64418. For example, the compounds of Examples 7, 27, 30, 31, 34, 35 and 38 have K I values of 24 nM, 16 nM, 22 nM, 11.5 nM, 11 nM, 10 nM and 4 nM in the assay.
    [75] With respect to their inhibition of adenosine A2b receptor activity and generally to their inhibition of adenosine A3 receptor activity, the compounds of formula I in free or pharmaceutically acceptable salt form (hereinafter also referred to as agents of the invention) Is useful for treating diseases mediated by activation of adenosine A2b receptors or adenosine A3 receptors, in particular inflammatory or allergic diseases. Treatment in accordance with the invention may be symptomatic or prophylactic.
    [76] Thus, the drugs of the present invention are useful for the treatment of inflammatory or obstructive airway disease, resulting, for example, in the reduction of tissue damage, airway inflammation, bronchial hyperresponsiveness, remodeling or the progression of the disease. Inflammatory or obstructive airway diseases to which the present invention is applied include endogenous (non-allergic) asthma and exogenous (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, bronchial asthma, occupational asthma, occupational Asthma caused after asthma and bacterial infections. The treatment of asthma also covers the treatment of patients with 4 or 5 or less infants who are diagnosed with whistle symptoms and diagnosed or flexed infants, which are the main medical perspective and established patient category of current development or early asthma. It may be understood that this particular asthmatic disease is referred to as whisper-infant syndrome for convenience.
    [77] The prophylactic effect in the treatment of asthma can be demonstrated by reduced frequency or severe symptomatic seizures, such as acute asthmatic or bronchial contractile seizures, improved lung function or improved airway hyperresponsiveness. This may also be demonstrated by the reduction of the need for treatment of other symptoms, ie, limiting or stopping the onset of symptomatic symptoms occurring or for the intended treatment, such as anti-inflammatory (eg corticosteroid) or bronchodilator treatment. . The prophylactic benefit of asthma may be evident especially in patients who are prone to morning dipping. Morning dipping is a recognized asthmatic syndrome and generally accounts for a significant percentage of asthma, for example an asthma attack at a time between about 4 to 6 am, i.e., substantially distant from any symptomatic asthma treatment generally administered in advance. It is characterized by.
    [78] Other inflammatory or obstructive airway diseases and diseases to which the present invention may be applied include acute lung injury (ALI), adult respiratory distress syndrome (ARDS), chronic obstruction of the lung, airway or lung disease (COPD, COAD or COLD), these Chronic bronchitis or dyspnea associated with, emphysema, as well as other medications, aggravation of respiratory hyperactivity as a result of special other inhaled medication. The present invention is also applicable to the treatment of all forms of bronchitis, such as acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. In addition, other inflammatory or obstructive airway diseases to which the present invention can be applied are frequently accompanied by all forms of pneumoconiosis (inflammatory, generally occupational lung disease, chronic or acute, or airway obstruction, caused by repeated inhalation of dust). Jim) and include, for example, aluminumosis, carbonosis, asbestos deposition, sepsis, chisel dropout, iron sedimentation, silicosis, tobacco poisoning and immunity.
    [79] With regard to their anti-inflammatory activity, in particular with regard to inhibition of eosinophil activity, the drugs of the present invention are also associated with eosinophil-related diseases such as eosinophilia, especially airway disease including hypereosinophilia affecting the airways and / or lungs. Eosinophils (including, for example, pathological eosinophilic infiltration of lung tissue), as well as, for example, Lffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infections (including tropical eosinophilia), bronchial lung aspergillus It is useful in the treatment of neutrophil-related diseases affecting the symptoms, nodular polyarteritis (including Church-Strauss syndrome), eosinophilic granulomas and drug reactions.
    [80] The drug of the present invention is also used for inflammatory or allergic diseases of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multi-shape, herpes dermatitis, scleroderma, vitiligo, irritable vasculitis, urticaria, bullous lacrimal swelling , Lupus erythematosus, pemphisus, bullous epidermal aquisita, and other inflammatory or allergic diseases of the skin.
    [81] The drug of the present invention also affects the sense of smell, including allergic rhinitis, including other diseases or disorders, especially eye diseases and disorders such as conjunctivitis, dry keratoconjunctivitis and spring conjunctivitis, with certain diseases or disorders having an inflammatory composition. Inflammatory diseases (eg, hemolytic anemia, dysplasia anemia, pure erythrocyte anemia and idiopathic anemia), in which the autoimmune response includes autoimmune hematological disorders or autoimmune hematological diseases Lupus erythematosus, Multiple chondritis, Sclerodoma, Wegener granulamatosis, Skin myositis, Chronic active hepatitis, Myasthenia gravis, Steven-Johnson syndrome, Idiopathic sprue, Autoimmune inflammatory Intestinal diseases (e.g. ulcerative colitis and Crohn's disease), endocrine opthalmopathy, Grave disease, sarcoidosis, alveolitis, Hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (front and rear), dry keratoconjunctivitis and spring keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (eg Useful with or without nephrotic syndrome, including minor metabolic nephropathy.
    [82] Other diseases or disorders that can be treated by the drugs of the present invention are induced by diabetes, such as type I diabetes mellitus (combustible diabetes) and type II diabetes mellitus, diarrhea disease, ischemia / reperfusion injury, diabetic retinopathy or hyperbaric oxygen. It is useful for the treatment of diseases characterized by retinopathy such as retinopathy and increased intraocular pressure or ocular secretion such as glaucoma.
    [83] The effectiveness of the drugs of the invention on the inhibition of inflammatory diseases, such as inflammatory airway disease, can be demonstrated in animal models such as mouse or rat models of airway inflammation or other mild disease. Such methods are described, for example, in Szarka et al., J. Immunol. Methods (1997) 202: 49-57; Renzi et al, Am. Rev. Respir. Dis. (1993) 148: 932-939; Tsuyuki et al., J. Clin. Invest. (1995) 96: 2924-2931; And Cernadas et al. (1999) Am. J. Respir. Cell Mol. Biol. 20: 1-8.
    [84] The invention also relates to co-therapeutic agents for use in combination with other drugs, such as anti-inflammatory agents, bronchodilators or antihistamine drug substances, in particular for use in the treatment of the above mentioned diseases of obstructive or inflammatory airway disease. It may be used to intensify or to reduce the required dose or to combine the possible side effects of the drug. The drug of the present invention may be mixed with other drugs in a fixed pharmaceutical composition or separately administered before, simultaneously, or after administration of another drug. Thus, the present invention encompasses the combination of the above-described drugs of the present invention with anti-inflammatory, bronchodilator or antihistamine drugs, wherein the drugs of the present invention and the drugs may be the same or different pharmacological compositions. The anti-inflammatory drugs are steroids, in particular glucocorticosteroids such as budesonide, beclamethasone, fluticasone, ciclesonide or mometasone, US5451700 LTB4 antagonists described, LTD4 antagonists such as montelukast and zafirlukast, cabergoline, bromocriptine, ropinirole and 4-hydroxy-7 Dopamine receptor agonists such as-[2-[[2-[[3- (2-phenylethoxy) propyl] -sulfonyl] ethyl] -amino] ethyl] -2 (3H) -benzothiazolone and medicaments thereof Scholarly acceptable salts (Viozan-hydrochloride of AstraZeneca), and Ariflo; GlaxoSmith Kline, Roflumilast; Byk Gulden, V-11294A (Napp), BAY19-8004 (Bayer), SCH PDE4 inhibitors such as -351591 (Schering-Plough), and PD189659 (Parke-Davis). The bronchodilators are anticholinergic or antimuscarinic drugs, in particular ipratropium bromide, oxitropium bromide and tiotropium bromide and salbutamol, terbutalin, salmeterol And, in particular, beta-2 adrenocepta agonists such as formoterol, pharmaceutically acceptable salts thereof, and compounds of formula I of PCT International Patent Publication No. WO 00/75114, incorporated by reference herein. (In free or salt or solvate form), preferably the compounds of the examples thereof, in particular the compounds of formula (X) and pharmaceutically acceptable salts thereof.
    [85]
    [86] Co-therapeutic antihistamine drugs include cetirizine hydrochloride, ecetoaminophen, clemastine fumarate, promethazine, loratidine, and desloratidine (desloratidine), diphenhydramine and fexofenadine hydrochloride. Combinations of drugs and steroids, beta-2 agonists, PDE4 inhibitors or LTD4 antagonists of the invention can be used, for example, in the treatment of COPD or in particular in the treatment of asthma. Combinations of drugs of the invention and anticholinergic or antimuscarinic drugs, PDE4 inhibitors, dopamine receptor agonists or LTB4 antagonists can be used in the treatment of asthma, or in particular COPD.
    [87] Other useful combinations of drugs of the invention with anti-inflammatory drugs are chemokine receptor antagonists such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8 , CCR-9 and CCR-5 antagonists such as CCR-10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, especially Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, N-[[4-[[[6 , 7-dihydro-2- (4-methylphenyl) -5H-benzocyclohepten-8-yl] carbonyl] amino] phenyl] -methyl] tetrahydro-N, N-dimethyl-2H-pyran-4-amimi Takeda antagonist, such as aluminum chloride (TAK-770), and US 6166037 (particularly Claims 18 and 19), WO 00/66558 (particularly Claim 8), and WO 00/66559 (particularly Claim 9) In combination with CCR-5 antagonists described in.
    [88] In accordance with the above, the present invention also relates to the administration of adenosine A2b receptor and / or adenosine A3 receptor, which comprises administering to a subject in need thereof, in particular to a human subject, in free form or in a pharmaceutically acceptable salt form. Methods of treating diseases mediated by activation, such as inflammatory or allergic diseases, in particular inflammatory or obstructive airway diseases, are provided. Another aspect of the invention relates to formula I in free form or in a pharmaceutically acceptable salt form for use in the manufacture of a medicament for the treatment of diseases mediated by adenosine A2b receptors and / or adenosine A3 receptors, in particular inflammatory or obstructive airway diseases. It provides a compound of.
    [89] The medicaments of the invention may be inhaled for the treatment of parenteral, eg, inflammatory or obstructive airway diseases, orally, such as intravenously in the form of all suitable routes, such as tablets or capsules; Intranasally, such as for the treatment of allergic rhinitis, topically to the skin for the treatment of atopic dermatitis; Or rectally, for example for the treatment of inflammatory bowel disease.
    [90] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) in free form or in the form of a pharmaceutically acceptable salt, optionally with a pharmaceutically acceptable diluent or carrier. The composition may comprise anti-inflammatory, bronchodilator or antihistamine in combination with the therapeutic agent. The composition can be prepared using conventional diluents or excipients and known techniques. The oral formulations include tablets and capsules. Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, eg patches. Compositions for inhalation may include aerosols or other sprayable formulations or dry granulated formulations.
    [91] The dosage of the agents of the invention used to practice the invention depends, of course, on the particular disease to be treated, the desired effect and the route of administration. In general, the preferred daily dose for oral administration is on the order of 0.1 to 10 mg / kg.
    [92] The present invention is described by the following examples.
    [93] Example 1-38
    [94] The compounds of formula (I) of the general formula are shown in the table below, the preparation of which is described below.
    [95]
    [96] The table also shows mass stacktrometry (MH +) data. The examples are in free form, with the exception of Examples 10 and 25, which are in the form of hydrobromic acid and salts, and Example 33, which is in the form of trifluoroacetic acid and salts.
    [97]
    [98]
    [99]
    [100]
    [101]
    [102]
    [103] Preparation of Specific Examples:
    [104] Example 12 N- [4- (3-cyano-phenyl) -5- [1,2,4] triazol-1-yl-thiazol-2-yl] -4-methoxy-benzamide
    [105] 4-methoxybenzoyl chloride (0.16 ml, 1.36 mmol) was added 3- (2-amino-5- [1,2,4] triazol-1-yl-thiazol-4-yl in dry pyridine (1.5 ml). To a solution of) -benzonitrile (0.15 g, 0.56 mmol). After stirring for 2 hours, the reaction mixture was triturated with hot ethanol for 30 minutes and then the solid was collected by filtration. The solid was washed with ethanol and dried to give the title compound, ms (MH < + >) 402, mp292-294 o C.
    [106] Examples 5, 9, 11 and 22 are similarly prepared.
    [107] Starting materials are prepared as follows:
    [108] 3- (2-Amino-5- [1,2,4] triazol-1-yl-thiazol-4-yl) -benzonitrile
    [109] 3- (2-Bromo-2- [1,2,4] triazol-1-yl-acetyl) -benzonitrile hydrobromide (1.848 g, 5.00 mmol), thiourea (0.46 g, 1.2 mol) in ethanol ) Was heated at 95 ° C. for 8 hours. The solvent was removed under vacuum to give a foam and dissolved in 3M hydrochloric acid. The product precipitated into white powder by addition of concentrated aqueous ammonia. pH 11.MS (MH <+>) 269.54.
    [110] Example 15 3- [2- (6-Methyl-pyridin-2-ylamino) -5- [1,2,4] triazol-1-yl-thiazol-4-yl] -benzonitrile
    [111] 3- (2-Bromo-2- [1,2,4] triazol-1-yl-acetyl) -benzonitrile hydrobromide (500 mg, 1.34 mmol) was dissolved in ethanol (5 ml). (6-Methyl-pyridin-2-yl) -thiourea (208 mg, 1.34 mmol) was added and the reaction was heated at 90 0 C for 2 hours. The precipitate was collected and washed twice with ethanol. The solid was suspended with water, basified with concentrated ammonia hydroxide, the resulting precipitate was collected and washed with water to afford the title compound and dried. Mass Spec (APCI +) 360.0, mp236-237 o C.
    [112] Thiouria starting material was prepared as follows:
    [113] (6-Methyl-pyridin-2-yl) -thiourea
    [114] 6-Methyl-pyridin-2-ylamine (1.0 g, 9.2 mmol) was dissolved in ethanol (10 ml) and benzoylisothiocyanate (1.24 ml, 9.2 mmol) was added dropwise. The mixture was heated to 40 0 C for 10 minutes with stirring and then cooled to room temperature. The solvent was removed in vacuo and the resulting solid was dissolved in 1M sodium hydroxide (15 ml) and heated at reflux for 2 hours. The resulting suspension is filtered, the solid is washed several times with water and then with cold ethanol. The solid was dried in vacuo to afford the title compound. Mass Spec (APCI +) 168.
    [115] Example 27 (3- [2- (pyrazin-2-ylamino) -5- [1,2,4] triazol-1-yl-thiazol-4-yl] -benzonitrile):
    [116] 3-([1,2,4] triazol-1-yl-acetyl) -benzonitrile (150 mg, 0.7 mmol) was dissolved in dioxane (640 l) and bromine (19 l) was added dropwise. The mixture was then heated at 80 0 C for 6 hours. The resulting suspension was cooled to room temperature and the precipitate was isolated by filtration. This precipitate, 3- (2-bromo-2- [1,2,4] triazol-1-yl-acetyl) -benzonitrile hydrobromide (200 mg, 0.5 mmol) was dissolved in ethanol (2 ml). Pyrazin-2-yl-thiourea (0.5 mmol) was added and the reaction was heated at 80 0 C for 10 h. Ethanol was removed in vacuo and the residue was fully powdered in 3M HCl. The resulting suspension was basified with concentrated ammonium hydroxide and the resulting precipitate was filtered off and washed with cold ethanol. The solid was thus obtained and dried in vacuo to afford the title compound, mp> 250 0 C, ms (AP +) 347.
    [117] Examples 3, 6-8, 10, 13-14, 17-18, 20-21, 24-26 and 28-31 were prepared in a similar manner from the appropriate compounds of formulas II and III.
    [118] Starting materials are prepared as follows:
    [119] 3-([1,2,4] triazol-1-yl-acetyl) -benzonitrile:
    [120] 3-cyanoacetophenone (10.013 g, 69 mmol) was dissolved in dioxane (150 ml) and bromine was added (3.53 ml). The mixture was stirred at room temperature for 30 minutes, the solvent was removed in vacuo and the residue was taken up in acetonitrile (100 ml). Sodium triazole (7 g) was added and the mixture was stirred at room temperature overnight. The mixture was then filtered and the solid obtained was collected. The precipitate was evaporated to dryness and the solid residue dissolved while heating in 3M HCl (500 ml). The aqueous layer was poured from the sticky residue and washed with ethyl acetate. The aqueous layer was basified with concentrated aqueous ammonia solution and the resulting precipitate was filtered off and washed with water. The precipitate was dried in vacuo to afford 3-([1,2,4] triazol-1-yl-acetyl) -benzonitrile, mp172-173 0 C, ms (AP +) 213.
    [121] Other compounds of formula II are prepared in a similar manner from suitable acetophenones.
    [122] Pyrazin-2-yl-thiourea:
    [123] Aminopyrazine (2 g, 21.03 mmol) was dissolved in ethanol (20 ml) and benzoylisothiocyanate (2.82 ml) was added dropwise. The mixture was heated to 80 0 C with stirring for 10 minutes and then cooled to room temperature. The solvent was removed in vacuo and the resulting solid was dissolved in 1M sodium hydroxide (30 ml) and heated at reflux for 1 h. The resulting suspension was filtered and the solid was washed with water and some cold methanol. The solid was dried in a long hole to afford the title compound, mp 239-239.5 o C, ms (AP +) 138 (M + −NH 3 ).
    [124] Other thioureas of formula III are prepared in a similar manner from suitable starting amines.
    [125] Example 35: (3- [5- (2-Methyl-imidazol-1-yl) -2- (pyrazin-2-ylamino) -thiazol-4-yl] -benzonitrile):
    [126] Mix 3- [5-bromo-2- (pyrazin-2-ylamino) -thiazol-4-yl] -benzonitrile (250 mg, 0.698 mmol) and 2-methylimidazole (573 mg, 6.98 mmol) And heated to melt at 150 0 C for 16 h. The resulting solid was purified by flash chromatography to give the title compound as a powder, mp276-276.5 0 C, ms 360 (TOF, ES +).
    [127] Examples 1, 2 and 32-34 are prepared by reacting suitable compounds of Formulas IV and V in a similar manner.
    [128] Starting materials are prepared as follows:
    [129] 3- [2- (pyrazin-2-ylamino) -thiazol-4-yl] -benzonitrile:
    [130] 3-acetylbenzonitrile (1.0 g, 6.88 mmol) was added to dioxane (15 ml) and bromine (353 l, 6.88 mmol) was added dropwise under constant stirring. The reaction was stirred for 30 minutes, after which the dioxane was evaporated under reduced pressure. The resulting slurry was placed in ethanol (15 ml) and pyrazinyl-2-thiourea (1.0 g, 6.88 mmol) was added. The reaction was then heated at 80 0 C for 30 minutes, cooled to room temperature and ethanol was distilled off under reduced pressure. The solid was suspended with 3M HCl and basified with ammonia solution. The resulting precipitate was filtered off and washed several times with water and cold ethanol. Very powdered with methanol and subsequently dried to give the title compound, mp203-204 0 C, ms280 (ES +).
    [131] 3- [5-Bromo-2- (pyrazin-2-ylamino) -thiazol-4-yl] -benzonitrile:
    [132] 3- [2- (pyrazin-2-ylamino) -thiazol-4-yl] -benzonitrile (1.5 g, 5.36 mmol) is suspended in hot glacial acetic acid (10 ml) and bromine (0.275 ml) is stirred at room temperature. Dropped at The resulting suspension was stirred at room temperature for 10 minutes. Water (ca. 100 ml) was added to the mixture and basified to pH 9 with solid potassium carbonate. The resulting precipitate was filtered and washed with water to afford 3- [5-bromo-2- (pyrazin-2-ylamino) -thiazol-4-yl] -benzonitrile, mp 215 0 C (dec.) , ms 279 (ES +, M + -Br).
    [133] Other compounds of formula IV are prepared in a similar manner from suitable compounds of formulas IX and III.
    [134] Example 36 1-Methyl-1H-pyrrole-2-carboxylic acid [4- (3-cyano-phenyl) -5- [1,2,4] triazol-1-yl-thiazol-2-yl] -amides
    [135] 1-Methyl-1H-pyrrole-2-carbonyl chloride (110 mg) was dried in 3- (2-amino-5- [1,2,4] triazol-1-yl-thiazole- in dry pyridine (0.5 ml). To a solution of 4-yl) -benzonitrile (50 mg, 0.19 mmol). After stirring for 16 hours, water (10 ml) was added. After 3 days, the precipitate was collected and washed with water. The resulting cake was powdered for 20 min in reflux ethanol, filtered and washed with ethanol. The solid was triturated with saturated aqueous sodium bicarbonate, filtered, washed with water and dried to afford the title compound. Mass Spec. (MH <+>) 376, mp245-247 o C.
    [136] Examples 4-5, 16, 19 and 23 are similarly prepared.
    [137] Example 37: 3- [2- (6-methoxy-pyrazin-2-ylamino) -5- [1,2,4] triazol-1-yl-thiazol-4-yl] benzonitrile
    [138] 3- (2-Bromo-2- [1,2,4] triazol-1-yl-acetyl) -benzonitrile hydrobromide (250 mg, 0.67 mmol) was dissolved in ethanol (2 ml). (6-methoxy-pyrazin-2-yl) -thiourea (0.67 mmol) was added and the reaction was heated to 80 0 C for 10 hours. Ethanol was removed in vacuo and the residue triturated with 3M HCl. The resulting suspension was basified with concentrated ammonium hydroxide and the resulting precipitate was filtered off and washed with water then cold ethanol. The solid thus obtained was triturated with hot ethanol and dried in vacuo to afford the title compound. Mass Spec (APCI +) 377.1.
    [139] Example 38 was prepared similarly.
    [140] Thiouria starting material is prepared as follows:
    [141] (6-methoxy-pyrazin-2-yl) -thiourea
    [142] 6-methoxy-pyrazin-2-ylamine (0.85 g, 6.8 mmol) was dissolved in ethanol (7 ml) and benzoylisothiocyanate (0.91 ml) was added dropwise. The mixture was heated to 80 0 C with stirring for 10 minutes and then cooled to room temperature. The solvent was removed in vacuo and the resulting solid was dissolved in 1M sodium hydroxide (15 ml) and heated at reflux for 1 h. The resulting suspension was filtered and the solid was washed with water and some cold ethanol. The solid was dried in vacuo to afford the title compound.
    [143] Example 39(3- [5- (2-methyl-imidazol-1-yl) -2- (pyrazin-2-ylamino) -thiazol-4-yl] -benzonitrile) methanesulfonate
    [144] (3- [5- (2-Methyl-imidazol-1-yl) -2- (pyrazin-2-ylamino) -thiazol-4-yl] -benzonitrile (lg, 2.78 mmol) was dissolved in hot pentanol Suspended in (25 ml) and filtered hot to give a clear solution: methanesulfonic acid (0.2 ml, 3.06 mmol) was added and the mixture was cooled to room temperature to precipitate a solid, diethyl ether (25 ml) was added with stirring The solid was filtered off, washed with diethyl ether and triturated with diethyl ether (25 ml) The resulting solid was filtered, dried in vacuo and suspended in hot acetone (20 ml). Acetone (5 ml) was then added and the resulting solution was cooled to 4 0 C. The resulting solid was filtered off, washed with acetone and dried at 80 0 C over P 2 0 5 in vacuo to afford the title compound, mp 282 0 C.
    [145] Starting materials are prepared as follows:
    [146] 3- (2-Methylimidazol-l-yl-acetyl) -benzonitrile
    [147] 3-acetylbenzonitrile (50 g, 0.345 mol) was dissolved in dioxane (600 ml) with stirring at room temperature, bromine (17.7 ml, 0.345 mol) was added and the mixture was stirred for 30 minutes. Dioxane was removed in vacuo to give a solid, which was dissolved in acetonitrile (300 ml). 2-methylimidazole (28.3 g, 0.345 mol) was added to the solution, the mixture was stirred for 1 hour, and the temperature of the mixture was raised to 45 0 C. The precipitated solid was filtered off, washed with acetonitrile and slurried with methanol for 1 hour. Filtration removes the insoluble solid, and the filtrate is evaporated in vacuo to give a solid, dried at 40 0 C, vacuum to give the title compound, ms 369 (MH <+>).
    [148] (3- [5- (2-Methyl-imidazol-1-yl) -2- (pyrazin-2-ylamino) -thiazol-4-yl] -benzonitrile):
    [149] 3- (2-methylimidazol-l-yl-acetyl) -benzonitrile (13.8 g, 0.06 mol) to pyrazinyl-2-thiourea (9.4 g, 0.06 mol), iodine (15.6 g, 0.06 mol) And pyridine (60 ml). The mixture was initially stirred at room temperature then at 60 0 C overnight (17.5 hours). The resulting mixture was cooled to room temperature and water (50 ml) was added. The solid obtained was filtered, stirred for 30 min in water (50 ml) and filtered again. The resulting solid was dried over 40 0 C on P 2 0 5 in vacuo to afford the title compound.
    权利要求:
    Claims (16)
    [1" claim-type="Currently amended] A compound of formula I in free or salt form:

    Wherein Ar is a monovalent aromatic group of C 6 -C 15 ,
    R 1 is hydrogen, halogen, cyano, hydroxy, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C Phenyl optionally substituted with one or more substituents selected from 8 -alkyl or acyloxy, or a 5- or 6-membered monovalent heterocyclic group,
    R 2 is hydrogen, C 1 -C 8 -alkyl, acyl or -CON (R 3 ) R 4 , provided that when R 1 is hydrogen, R 2 is C 1 -C 8 -alkyl, acyl or -CON (R 3 ) R 4 ,
    R 3 and R 4 each independently represent hydrogen or C 1 -C 8 -alkyl, or a 5- or 6-membered heterocyclic group together with the nitrogen atom to which they are attached,
    Z 1 , Z 2 , Z 3 and Z 4 are each independently N or CR 5 , at least one of them is CR 5 ,
    R 5 is hydrogen, C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy.
    [2" claim-type="Currently amended] The compound of claim 1, wherein Ar is phenyl optionally substituted by one or more substituents selected from halogen, cyano, C 1 -C 8 -alkyl or C 1 -C 8 -haloalkyl.
    [3" claim-type="Currently amended] The compound of claim 1, wherein Ar is phenyl optionally substituted with halogen, cyano or C 1 -C 8 -alkyl in the meta or para position relative to the thiazole ring.
    [4" claim-type="Currently amended] A compound according to claim 1, 2 or 3, wherein R 1 is hydrogen, cyano or phenyl optionally substituted by C 1 -C 4 -alkoxy, or a monovalent 6-membered N-heterocyclic group. .
    [5" claim-type="Currently amended] 5. The compound of claim 1, wherein R 2 is hydrogen, C 1 -C 4 -alkylcarbonyl, C 3 -C 6 -cycloalkylcarbonyl, phenylcarbonyl, wherein the phenyl group is C 1 Optionally substituted by -C 4 -alkoxy, or heterocyclylcarbonyl, wherein the heterocyclyl group is 5- or 6-membered and has a ring hetero atom selected from nitrogen, oxygen and sulfur .
    [6" claim-type="Currently amended] The compound of claim 1, wherein Ar is phenyl optionally substituted by halogen or cyano,
    R 1 is hydrogen, cyano or phenyl optionally substituted by C 1 -C 4 -alkoxy, or a monovalent 6-membered N-heterocyclic group,
    R 2 is hydrogen, C 1 -C 4 -alkylcarbonyl, C 3 -C 6 -cycloalkylcarbonyl, phenylcarbonyl, wherein the phenyl group is optionally substituted by C 1 -C 4 -alkoxy, or Heterocyclylcarbonyl, wherein the heterocyclyl group is 5- or 6-membered and has 1 or 2 ring heteroatoms selected from nitrogen, oxygen and sulfur,
    Z 1 and Z 3 each represent N, Z 2 and Z 4 each represent CH, or Z 1 represents CR 5 , wherein R 5 is hydrogen or C 1 -C 4 -alkyl, Z 2 Represents N, and Z 3 and Z 4 each represent CH.
    [7" claim-type="Currently amended] The compound of claim 1, wherein Ar is phenyl in which the meta or para position is substituted with halogen or cyano with respect to the thiazole ring,
    R 1 is a monovalent 6-membered N-heterocyclic group,
    R 2 is hydrogen,
    Z 1 and Z 3 each represent N, Z 2 and Z 4 each represent CH, or Z 1 represents CR 5 , wherein R 5 is hydrogen or C 1 -C 4 -alkyl, Z 2 Represents N, and Z 3 and Z 4 each represent CH.
    [8" claim-type="Currently amended] The compound of claim 1, wherein Ar is phenyl in which the meta or para position is substituted by halogen or cyano with respect to the thiazole ring,
    R 1 is hydrogen,
    R 2 is phenylcarbonyl, wherein phenyl is optionally substituted by C 1 -C 4 -alkoxy, or heterocyclylcarbonyl, wherein the heterocyclyl group is 5- or 6-membered, oxygen and sulfur Has a ring hetero atom selected from
    Z 1 and Z 3 each represent N, Z 2 and Z 4 each represent CH, or Z 1 represents CR 5 , wherein R 5 is hydrogen or C 1 -C 4 -alkyl, and Z 2 is N represents, and Z 3 and Z 4 each represent CH.
    [9" claim-type="Currently amended] A compound of formula XI in free or salt form:

    Here, R a , R b , R 1 , R 2 , Z 1 , Z 2 , Z 3 and Z 4 are as shown in the following table.




    [10" claim-type="Currently amended] The compound according to claim 1, for use as a medicament.
    [11" claim-type="Currently amended] The compound of any one of claims 1-10, in combination with an anti-inflammatory, bronchodilator or antihistamine drug, wherein the compound and the drug are in the same or different pharmacological composition.
    [12" claim-type="Currently amended] A pharmaceutical composition comprising the compound of any one of claims 1-11 as an active ingredient, optionally with a pharmaceutically acceptable diluent or carrier.
    [13" claim-type="Currently amended] Use of a compound of any one of claims 1 to 11 for the manufacture of a medicament for the treatment of a disease mediated by the activation of adenosine A2b receptors.
    [14" claim-type="Currently amended] Use of a compound of any one of claims 1 to 11 for the manufacture of a medicament for the treatment of a disease mediated by activation of the adenosine A3 receptor.
    [15" claim-type="Currently amended] Use of a compound of any one of claims 1 to 11 for the manufacture of a medicament for the treatment of inflammatory or obstructive airway disease.
    [16" claim-type="Currently amended] (i) (A) For the preparation of compounds of formula I wherein R 1 is optionally substituted with phenyl or a 5- or 6-membered heterocyclic group, the compounds of formula II in salt form React with a compound of
    (B) For the preparation of compounds of formula (I), wherein R 1 is optionally substituted with phenyl or a 5- or 6-membered heterocyclic group, a compound of formula (IV) is combined with a compound of formula (V) React,
    (C) To prepare a compound of formula (I) wherein R 2 is acyl or -CON (R 3 ) R 4 , the compounds of formula (VI) are respectively converted to acylated derivatives of 3 ) reacts with the compound of R 4 ),
    (ii) recovering the compound of formula (I) in the form of free or salt
    Process for preparing compounds of formula (I) in free or salt form comprising:





    Wherein Ar, Z 1 , Z 2 , Z 3 , Z 4 , R 3 , R 4 are as defined in claim 1,
    X is halogen,
    In Formulas III and IV, R 1 is halogen, cyano, hydroxy, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy- Phenyl optionally substituted with one or more substituents selected from C 1 -C 8 -alkyl and acyloxy, or R 1 is a 5- or 6-membered monovalent heterocyclic group, and R 2 is H or C 1 -C 8 -Alkyl,
    R 1 in formula VI is as defined in claim 1.
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    同族专利:
    公开号 | 公开日
    US7109202B2|2006-09-19|
    AT300536T|2005-08-15|
    BR0115478A|2004-02-17|
    JP3973556B2|2007-09-12|
    ECSP034611A|2003-06-25|
    GB0028383D0|2001-01-03|
    NO20032277L|2003-07-21|
    US20040053982A1|2004-03-18|
    CN1244580C|2006-03-08|
    CA2429442A1|2002-05-30|
    SK6032003A3|2004-01-08|
    AR035371A1|2004-05-12|
    PE20020580A1|2002-08-13|
    CZ20031393A3|2003-08-13|
    JP2004521871A|2004-07-22|
    NO20032277D0|2003-05-20|
    AU3722102A|2002-06-03|
    HU0302079A2|2003-09-29|
    RU2003117476A|2005-02-10|
    CN1476447A|2004-02-18|
    EP1339711A1|2003-09-03|
    DE60112322D1|2005-09-01|
    EP1339711B1|2005-07-27|
    ES2246346T3|2006-02-16|
    IL155712D0|2003-11-23|
    MXPA03004439A|2003-08-19|
    WO2002042298A1|2002-05-30|
    NZ525875A|2004-11-26|
    ZA200303721B|2004-05-10|
    DE60112322T2|2006-05-24|
    PL361842A1|2004-10-04|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-11-21|Priority to GB0028383.8
    2000-11-21|Priority to GBGB0028383.8A
    2001-11-19|Application filed by 노파르티스 아게
    2001-11-19|Priority to PCT/EP2001/013378
    2004-01-24|Publication of KR20040007412A
    优先权:
    申请号 | 申请日 | 专利标题
    GB0028383.8|2000-11-21|
    GBGB0028383.8A|GB0028383D0|2000-11-21|2000-11-21|Organic compounds|
    PCT/EP2001/013378|WO2002042298A1|2000-11-21|2001-11-19|Aminothiazoles and their use as adenosine receptor antagonists|
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