TW200813056A - Adenosine A2B receptor antagonists - Google Patents

Abstract

The present invention provides compounds of the formula (1): which are adenosine A2B receptor antagonists and, thus, may be employed for the treatment of conditions and diseases mediated by the adenosine A2B receptor activity. Such conditions include, but are not limited to, chronic and acute inflammatory diseases involving degranulation of mast cells, e.g., asthma, allergic rhinitis and allergic dermatitis; impaired sensitivity to insulin, e.g., type 2 diabetes, non-insulin dependent diabetes, pre-diabetic state, and impaired glucose tolerance; diseases in which angiogenesis is a key component of pathogenesis, e.g., solid tumors and angiogenic retinopathies; apnea of preterm infants; myocardial reperfusion injury; inflammatory bowel disease; autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and lupus erythematosis; diseases involving microvascular abnormalities of the retina that are mediated by adenosine A2B receptors, e.g., retinopathy of prematurity, macular degeneration, and diabetic retinopathy; and cardiac diseases including hyperplasia consequent to hypertension, arteriosclerosis, and heart attack.

Description

200813056 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD The present invention relates to 8-pyrazole-xanthine derivatives, pharmaceutical compositions containing the same, and treatment by adenosine Am by using the compounds Methods of mediated diseases and diseases. SUMMARY OF THE INVENTION Accordingly, the present invention provides a compound of the formula

among them

Ri and R2 are each independently a CrC6 alkyl group, which is optionally substituted by CVC4 alkoxy, c3-C6 cycloalkyl, c2_C4 alkenyl, C2-C4 alkynyl or optionally 1 to 3 Monocyclic aryl groups substituted with substituents of the following groups of groups: Cl-C4 alkyl, trifluoromethyl, dentyl, thiol, cvcu alkoxy, methylenedioxy, thiol, Cl_c4 Alkylthio, cyano, carboxyl, d-C4 alkoxycarbonyl, Cl_C4 alkylthiocarbonylalkylsulfonyl; R3 is hydrogen or halogen; R4 and Rs are each independently hydrogen or Cl-c4 alkyl; R6 An aryl or heteroaryl group, each of which may optionally be substituted with 1 to 3 substituents selected from the group consisting of: Cl-C6 alkyl, trifluoromethyl, C3_C6 cycloalkyl, halo, Hydroxy, Cl-C6 alkoxy, methylene 120857.doc 200813056 Dioxy, ethylenedioxy, alkanoyl, alkoxy, C6-C1() aryloxy, amine, cKC6 alkylamine Base, bis(cKc6 alkyl)amine, thiol, C^-Cg alkylthio, C6-Cig arylthio, nitro, cyano, carboxyl, CrG alkoxycarbonyl, amine carbhydryl, • (VC6 alkylthiocarbonyl, Cl_c0 alkane Sulfosyl or C0_Ci()-sulfonyl; or a pharmaceutically acceptable salt thereof. The compound of the present invention is an adenosine Am receptor antagonist, and thus is useful for the treatment of adenosine An receptor activity. Conditions and diseases including, but not limited to, chronic and acute inflammatory diseases involving mast cell degranulation, such as asthma, allergic rhinitis and atopic dermatitis; abnormal sensitivity to insulin, such as type 2 diabetes, non-insulin Dependent diabetes, diabetes status, and glucose tolerance; diseases with angiogenesis as a key cause of disease, such as solid tumors and angiogenic retinopathy; premature infant apnea; myocardial reperfusion injury; inflammatory bowel disease Autoimmune U disease, such as rheumatoid arthritis, multiple sclerosis, and lupus erythematosus; diseases involving retinal microvascular abnormalities mediated by adenosine scorpion receptors, such as retinopathy of prematurity, macular degeneration, and diabetes Retinopathy; and heart disease 'including hyperplasia caused by high blood pressure, arteriosclerosis and heart attack. This issue: 8, azole _ Anthraquinone derivatives can also be used as radioligands; the biological activities associated with adenosine receptors (especially adenosine A2b receptors). The first month has revealed some 8_0 ratios. An albazole-xanthine derivative as described in U.S. Patent Nos. 7,205,403 and 6,825,349. [Embodiment] The compounds listed below for the description of the present invention are listed below. Definitions of various terms. Unless such definitions are otherwise limited in a particular case or as part of a larger group, such definitions apply to such terms throughout the specification. "Alkyl substituted by alkylation" means an unsubstituted or substituted alkyl group having from 1 to 20 atoms, preferably from 1 to 1 atom, more preferably to an anti-atom. A chain or branched hydrocarbon group. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, g. Base, 4,4-dimethylpentyl, octyl and the like. The substituted alkyl group includes, but is not limited to, an alkane substituted with one or more (preferably 1 to 3) groups Base: _ group, hydroxy, alkano group, alkoxy group, cycloalkyl group, cycloalkyloxy group, alkoxy group, material, alkylthio group, alkylthiocarbonyl group, sulfonyl group, amidoxime group, Aminomethyl, cyano, thiol, fluorenyl 'aryl, aryloxy, alkenyl, alkynyl, aryl alkoxy, fluorenyl, optionally substituted amine, heterocyclic (including imidazole) a group, a furyl group, a thienyl group, a thiazolyl group, a pyrrolidinyl group, a pyridyl group, a pyrimidinyl group, and the like. The term "lower alkyl group" means having 1 to 6, preferably 2 to 4 Carbon atom The alkyl group by them. The term 'alkenyl" refers to any alkyl group having at least two carbon atoms and further containing a carbon-carbon double bond at the point of attachment. 120857.doc 200813056 group having 2 to 4 carbon atoms is preferred The term "fast radical" refers to any alkyl group having at least two carbon atoms and further having a slave-bonded bond at the point of attachment. A group having 2 to 4 carbon atoms is preferred. "吾alkyl" means a straight-chain bridge of 1 to 6 carbon atoms connected by a single bond, for example -(CH2)x...wherein X is 1 to 6, and in the case where χ is greater than 丨, the chain may be miscellaneous One or more heteroatoms selected from the group consisting of hydrazine, S, S(O), s(0)2, CH=CIi, C=C or NR, wherein R can be hydrogen, alkyl, alkenyl, alkynyl, J Alkyl, aryl, heterocyclic, aralkyl, heteroaralkyl, anthracenyl, aminemethanyl 'anthracenyl, alkoxy (tetra), aryloxy or aryloxyalkyl and a similar group; and the alkyl group may further be subjected to one or more alkyl, cycloalkyl, aryl, heterocyclic, pendant oxy, _, s, carboxy, alkane, optionally substituted Oxyl, alkoxycarbonyl and the like The substituent of the group is substituted. The term "cycloalkyl" refers to an optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon group having from 3 to 12 carbon atoms, each of which may contain one or more carbon-carbon double bonds, or a cycloalkyl group may be used. Substituted by one or more substituents such as alkyl, halo, pendant oxy, hydroxy, alkoxy, alkyl fluorenyl, decylamino, amidino, alkylamino, dialkylamino, sulphur Alcohol, alkylthio, cyano, carboxyl, alkoxycarbonyl, sulfonyl, sulfonylamino, sulfonyl, heterocyclic, and the like. Exemplary monocyclic nicotine includes (but not It is limited to cyclopropyl, cyclobutyl, cyclopentylcyclopentanyl, cyclohexyl, cyclohexyl, 4,4-dimethylcyclohex-1-yl, cyclooctenyl and the like. 120857.d〇, -10- 200813056 #非非性双环基基基 includes anthracenyl, fluorenyl, hexahydroindenyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2丄1]hexyl, bicyclo[2.2 .1] heptyl, double ¥[2.^1] heptyl, 6,6-diindenylbicyclo[3.1.1]heptyl, 2,6,6-trimethyl bis, [3.1.1] Heptyl, bicyclo[2 2 2]octyl and the like. The non-volatile tricyclic nicotine includes diamond a group or a similar group. In the definitions listed in the text, the term "when used as a term" refers to a base or a block of a calcined base, and also means a substituted alkyl group, a cycloalkyl group, Alkenyl or alkynyl. (The term "alkoxy" refers to the base-〇_. The term "cycloalkoxy" means cycloalkyl-Ο-. The term "burning thiol" means burning The term {(〇)_. The term "cycloalkane" refers to cycloalkyl-(:(〇)_. The term "alkenyl" refers to alkenyl-C(〇)_. The term ''alkynyl' 'Alkynyl-c(〇)_. The term "calcined oxy" refers to alkyl-C (0>0. (; term ', alkylamino, and, dialkylamino) , respectively, refers to alkyl-NH- and (alkyl) 2N_. The term "alkylalkylamino" means alkyl-C(0)-NH-. The term "alkylthio" means an alkane -S-. The term "dialkyl-based alkyl" refers to (alkyl) 3 S i -. The term "alkylalkyl alkoxy" means (alkyl) 3Si〇-. The term '' Alkylthiocarbonyl '' means alkyl-s(0)-. The term π calcining base refers to alkyl-S(0)2-. The term "alkoxycarbonyl " refers to alkyl-OC(O)-. 120857.doc -11- 200813056 The term "π alkoxycarbonyloxy" refers to alkyl-oc(o)o-. The term 11-aminomethylthio" Refers to H2NC(0)-, alkyl-NHC(O)-, (alkyl) 2NC(0)-, aryl-NHC(O)-, alkyl (aryl)-NC(0)-, heteroaryl -NHC(O)-, alkyl (heteroaryl)-NC(O)-, aralkyl-NHC(O)-, alkyl (aralkyl)-NC(O)- and the like . The term π-aminosulfonyl '' refers to h2ns(o)2-, alkyl-nhs(o)2-, (alkyl)2NS(0)2-, aryl-NHS(0)2-, alkyl (aryl)-NS(0)2-, (aryl)2NS(0)2-, heteroaryl-nhs(o)2-, aralkyl-nhs(o)2-, heteroaralkyl- Nhs(o)2- and its analogous groups. The term "sulfonamide" refers to alkyl-s(o)2-nh., aryl-s(o)2-nh-, aralkyl-s(o)2-nh-, heteroaryl -s(o)2-nh-, heteroaralkyl-s(o)2-nh-, alkyl-s(o)2-n(alkyl), aryl-s(o)2-n( Alkyl)-, aralkyl-s(o)2-n(alkyl)-, heteroaryl-s(o)2-n(alkyl)-, heteroaralkyl-s(o)2- n(alkyl)- and the like. The term "π sulfonyl" refers to alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroarylalkyl Sulfonyl and its like. The term "optionally substituted amino group π" refers to a first or second amino group optionally substituted with a substituent such as a fluorenyl group, a sulfonyl group, an alkoxycarbonyl group or a cycloalkoxycarbonyl group. , aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl, aminemethantyl and the like. The term "aryl" means 6 to 12 carbons in the ring portion. Monocyclic or bicyclic aromatic hydrocarbon groups of the atom, such as phenyl, biphenyl, naphthyl and tetrahydronaphthyl, each of which may be optionally substituted with from 1 to 4 substituents such as, for example, 120857.doc -12 - 200813056 Substituted alkyl, trifluoromethyl, optionally substituted cycloalkyl, halo, hydroxy, alkoxy, methylenedioxy, ethylenedioxy, decyl, alkoxy , aryloxy, optionally substituted amine, thiol, alkylthio, arylthio, nitro, cyano, carboxy, alkoxycarbonyl, aminecaraki, alkylthiocarbonyl, sulfonate a mercapto group, a sulfonylamino group, a heterocyclic group, and the like. The term "monocyclic aryl" means as described above for an aryl group. a substituted phenyl group. The monocyclic aryl group is preferably substituted with from 1 to 3 substituents selected from the group consisting of a functional group, a cyano group or a trifluoromethyl group. In the definitions set forth herein, as a term When a part refers to an aryl group, it also means a substituted aryl group. The term 'f aralkyl group' refers to an aryl group directly bonded via an alkyl group, such as a benzyl group. The term π aralkyl fluorenyl '' Refers to aralkyl-c(o)-. The term π aralkylthio "' refers to aralkyl-S-. The term 'aralkyloxy" refers to an aryl group bonded directly via an alkoxy group. The term "arylsulfonyl" refers to aryl-s(o)2_. The term "arylthio" refers to aryl-S-. The term ''aryl" refers to aryl-c(o) -. The term "aryloxy" refers to aryl-c(o)-o-. The term "arylamino" refers to aryl-C(0)-NH-. The term 'aryloxycarbonyl" refers to aryl-OC(O)-. The term "heterocyclyl" or "heterocycle" refers to a fully saturated or unsaturated, aromatic or non-aromatic ring group, for example A 4 to 7 membered monocyclic ring, a 7 to 12 membered bicyclic ring or a 10 to 15 membered three-soil system having at least one hetero atom in the ring containing at least one carbon atom to 120857.doc -13 - 200813056. Each ring of the heterocyclic group containing a hetero atom may have 1, 2 or 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and nitrogen and a sulfur atom may also be oxidized as appropriate. The heterocyclic group may be attached at a hetero atom or a carbon atom. Exemplary monocyclic heterocyclic groups include π each fluorenyl. Biloyl, 0 to sigma, propylene oxide, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, trisal. Oxime, oxazolidinyl, isoxazolidinyl, isoxazolyl, thiophanyl, fluorenyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuranyl, thiophene Base, oxadiazolyl, piperidinyl, piperazinyl, 2-sided oxypiperazinyl, indolyloxypiperidinyl, 2-side pi-pyrrolidyl, 2-sided oxy-nitrogen Alkyl, azirretyl, 4-bukenone, σ-bite, oxazino, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl Sulfone, thiamorpholinyl hydrazine, hydrazine, 3-dioxolane and tetrahydro-1 1,1-di-oxythiophenyl, 1,1,4-tri-oxy-1,2,5-thiadi Azolidin-2-yl and the like. Exemplary bicyclic heterocyclic groups include fluorenyl, indanyl, benzothiobenyl, benzoxazinyl, benzofluorenyl, benzoxenyl, benzoxazinyl, acridine , quinalhenyl, tetrahydroquinolinyl, decahydroquininyl, isoquinolinyl, tetradecylisoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, benzindene, fluorenyl Azinyl, benzofuranyl, chromenyl, coumarinyl, benzoxanyl, porphyrinyl, quinoxalinyl, oxazolyl, pyrroloindoleyl, furo-pyridinyl (such as furan) And [2,3-c] acridine, furo[3,2讣]•pyridyl] or indolo[2,3_b]indenyl), dihydroisoindole, iH- σ呤 · 120857.doc -14- 200813056 2,6(3H,7H)_dione, u di-side oxydihydroisoindole_2-yl, dihydro-glycolyl (such as 3,4·2 Hydrogen-4-oxo-quinazolinyl), pyridazinyl and the like. Non-standard bicyclic heterocyclic groups include carbazolyl, dibenzoazepine, dithienohamoyl, benzocyclo, morpholinyl "acridinyl, phenanthryl, morphyl , "N-based base and its similar groups. The term "heterocyclyl" refers to the heterocyclic group described above which is substituted by i, 2 or 3 substituents selected from the group consisting of: (a) as appropriate (b) a trans-group (or a protected radical); (c) a halo group; (d) a pendant oxy group, ie = hydrazine; (e) an optionally substituted amine group; (f) an alkane (g) a cycloalkyl group; (h) a carboxyl group; (1) a heterocyclic oxy group; (j) an alkoxy group, such as an unsubstituted (k) thiol; (1) a nitro group; Oxycarbonyl (m) cyano; (η) amine sulfonyl; (〇) decyloxy; (Ρ) aryl methoxy; 120857.doc 200813056 (q) arylthio; (r) aryloxy (s) alkylthio; (1) formic acid; (u) aminyl; (V) aralkyl; and (W) optionally alkyl, cycloalkyl, alkoxy, thiol, An aryl group substituted with an amine group, a decylamino group, an alkylamino group, a dialkylamino group or an ιδ group. ί ^ The term ''heterocyclicoxy group' means a heterocyclic group bonded via an oxygen bridge. The term 'heterocycloalkyl π' refers to a non-aromatic heterocyclic group as described above. The term ''heteroaryl π' refers to an aromatic heterocyclic ring, such as a monocyclic or bicyclic aryl group, such as σ-l- yl, sylphinyl, sulphate, triterpene, chelate, s Sitrate, oxime, isopropion, thiol, fluorenyl, σ, sigma, sigma, sulphate, sulfhydryl, sulfhydryl, benzoxanthyl, benzene And a benzothiophene group, a quinolyl group, an isoquinolyl group, a benzimidazolyl group, a benzof-anthranyl group and the like, which are optionally, for example, halogen, cyano, or schiffki. , trifluoromethyl, lower alkyl or lower alkoxy substituted. The term π heterocycloalkyl fluorenyl refers to heterocycloalkyl-C(O)-. The term "heteroarylsulfonyl' refers to heteroaryl-S(0)2-. The term "hetero醯基'' means heteroaryl-C(O)-. The term π heteroarylamino π means heteroaryl-C(0)NH-. The term π heteroarylalkyl f' means via alkyl Bonded heteroaryl. The term "heteroaralkyl fluorenyl n refers to heteroaralkyl-C(O). The term πheteroarylalkylamine" refers to heteroaralkyl-C(0) NH-. 120857.doc -16- 200813056 The term "mercapto," refers to alkyl hydrazino, cycloalkyl fluorenyl, olefin fluorenyl, alkynyl fluorenyl, aryl fluorenyl, heterocycloalkyl fluorenyl, heteroaryl fluorenyl, Aralkyl fluorenyl, heteroaralkyl fluorenyl and the like. The term "substituted sulfhydryl" refers to the sulfhydryl groups described above, wherein alkyl, % alkyl, alkenyl, alkynyl, aryl, heterocycloalkyl, heteroaryl, aromatic The alkyl or heteroarylalkyl group is substituted as described above, respectively. The term "mercaptoamine" refers to an alkanoamine group, an arylamino group, a heteroarylamine group, a sulfonylamine group, a heteroarylamine group, and the like. The term 'halogen' or , "halo" means fluorine, chlorine, bromine and iodine. The pharmaceutically acceptable salt of the compound of the present invention means a salt formed with an acid, that is, a salt such as a mineral acid, an organic carboxylic acid, and an organic sulfonic acid (for example, hydrochloric acid, maleic acid, and methanesulfonic acid, respectively). Acid addition salt. Similarly, a pharmaceutically acceptable salt of a compound of the present invention refers to a salt formed with a base, that is, a cationic salt such as an alkali metal salt and an alkaline earth metal salt such as a sodium salt, a lithium salt, a potassium salt, a calcium salt and a magnesium salt. a salt; and an ammonium salt such as an ammonium salt, a trimethylammonium salt, a diethylammonium salt, and a hydroxymethyl-indenyl-ammonium salt; and a salt formed with an amino acid, the limiting condition being an acidic group The group forms part of the structure. As described above, the present invention provides 8-pyrazole-xanthine derivatives of the formula (1), pharmaceutical compositions containing the derivatives, methods of preparing the compounds, and administration of a therapeutically effective amount of a compound of the invention or A pharmaceutical composition thereof for treating a condition mediated by adenosine a1b receptor, including but not limited to chronic and acute inflammatory diseases involving mast cell degranulation, such as asthma, allergic rhinitis, and atopic dermatitis Sensitivity to insulin 120857.doc -17- 200813056 Abnormalities, such as type 2 diabetes, non-insulin-dependent diabetes mellitus, pre-diabetic state, and impaired glucose tolerance; diseases with angiogenesis as a key cause of disease, such as solid tumors And angiogenic retinopathy; premature infant apnea; myocardial reperfusion injury; inflammatory bowel disease; autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and lupus erythematosus; involved by adenosine Azb receptor Diseases of the retinal microvascular abnormalities, such as retinopathy of prematurity, macular degeneration and diabetic retinopathy; and heart disease Including caused by the proliferation of high blood pressure, atherosclerosis and heart attack. Preferred are compounds of formula (I) wherein R3 is hydrogen; or a pharmaceutically acceptable salt thereof. Further preferred are compounds of formula (I) wherein R5 is hydrogen; R6 is a monocyclic aryl group which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of CKC6 alkyl, three Fluoromethyl, C3-C6 cycloalkyl, halo, hydroxy, Cl-C6 alkoxy, methylenedioxy, ethylenedioxy, (VQ alkanoyl, CVC6 alkoxy, c6-Cio Aryloxy, amine, CVC6 alkylamino, bis(CVC6 alkyl)amine, thiol, CkG alkylthio, C6-C1()arylthio, nitro, cyano, carboxyl, CrQ Alkoxycarbonyl, aminyl, (^-(alkylthiowei), Ci-C^, or C6-CiG aryl thiol; or a pharmaceutically acceptable salt thereof. More preferably, it is a compound of formula (I) wherein

Ri and R2 are each independently a Ci_C3 alkyl group optionally substituted by cyclopropyl, -CH=CH2, 120857.doc -18-200813056-bCH or phenyl; or a pharmaceutically acceptable salt thereof. The most preferred are compounds of formula (I) wherein R4 is methyl; or a pharmaceutically acceptable salt thereof. Depending on the nature of the substituent, the compound of the date of the month may have - or more

center,. The resulting diastereomers, optical isomers (i.e., enantiomers) and geometric isomers, as well as mixtures thereof, are encompassed by the present invention. A specific embodiment of the invention is: 2-[M2,6-di- oxy-π-dipropyl-2,3,6,7-tetra-n-n-n-whenyl)-5-methyl-saltyl]homben -Ethylamine; 2_[3_(2,6-di-oxy-dipropyl'-indolyl-heteroquinone)_5-methyl-pyranyl-yl]-Ν_(4· Base)-acetamide; [(2,6-side oxyd,% dipropyl-2,3,6,7-tetrahydroindenyl)-5-methyl-D ratio m]_N_(4_苯基 phenyl) acetamidine; [3 (2,6·-sideoxy q,% dipropyl-2,3,6,7-tetrahydro-ih_fluorenyl)_5_methyl_σ-biazole "-based"_Ν_(4·gasphenyl)_acetamide; 2 [3 (2'6_oneoxy-13-dipropyl-2,3,6,7-tetrahydro-111_嘌呤) -8-yl)5-methyl^ ratio. Sodium]-n-(4-fluorophenyl)-acetamidamine; ('6-^ oxy-1,3-dipropyl-.,,, -tetrahydro-^-嗓吟-^·yl)-5-methyl-pyrazole•methoxyphenyl)-acetamide; 2 [3 gas 2,6·di-oxy-L3-dipropyl 2·3,6,7-tetrahydro_1H-indole_8-yl)·5-methyl-pyrazolyl]_n_(3,4•dimethylphenyl>acetamide; 2 [ 3_(2,6·dioxaoxy-13-dipropyl-2,3,6,7-tetrahydro-111-嘌呤_8-120857.doc -19- 200813056 base)-5-methyl- Azole-1·yl]-N-(3,4-dimethoxyoxyphenyl)-acetamide; 2-[3-(2,6-di-oxy-1,3-dipropyl-2 ,3,6,7 - four mice_1Η-σ票吟-8-yl)-5-ethyl^bizozol-1-yl]-indole-(4-phenylphenyl)acetamidine; 2-[ 3-(2,6-di-branched-1,3-dipropyl-2,3,6,7-four-rat-111-嗓σ-8-base)-σ ratio ° sits -1 -yl] -Ν - (4-Phenylphenyl)-Ethylamine, 2-[3·(2,6-di-mercapto-1,3-dipropyl-2,3,6,7-four-rat-1Η-嗓ϋ-8-yl)-5-methyl-π-biazole_1_yl]-Ν-(4-dimethylaminophenyl)-acetamide; 2-[3_(2,6-two side Oxy-1,3-dipropyl-2,3,6,7-tetrahydro-111-嘌呤-8-V5-formamidine-pyridinium-1-one 1-Ν-Μ-篦二丁篡芄篡V acetamide; 2-[3-(2,6-di- oxy-1,3-dipropyl-2,3,6,7-tetrahydro-1Η-嘌呤-8-yl)- 5-methyl-0-thin-1 -yl]-indole-(na-1-yl)-ethonamide, 2-[3-(2,6-di-oxy-1,3-dipropyl- 2,3,6,7-tetrahydro-111-fluoren-8-yl)-5-methyl-η-pyrazol-1-yl]-indole-(3-decyloxyphenyl)-acetamide; 2-[3-(2,6-di-oxy-1,3-1,3-dipropyl-2,3,6,7-tetrahydro-1Η-嘌呤-8.yl)-5-methyl-n ratio Zin-1-yl]-indole-(3-chlorophenyl)-acetamidine ; 2-[3-(2,6-di- oxy-1,3-dipropyl-2,3,6,7-tetrazo-111-fluoren-8-yl)-5-methyl^ Biazolyl-1-yl]-indole-(3,4-dichlorophenyl)-acetamidamine; 2-[3-(2,6-di-oxo-1,3-dipropyl-2, 3,6,7-tetrahydro-1Η-嘌呤-8-yl)-5-mercapto-pyrazol-1-yl]-indole-p-tolyl-acetamide; 2-[4-chloro·3_( 2,6-di-oxy-1,3-dipropyl-2,3,6,7-tetrahydro-1H-inden-8-yl)-5-methyl-° ratio σ sitting-1 ]]-N - ( 4 · gas phenyl)-ethylamine, 2-[4-bromo-3-(2,6-di- oxy-1,3-dipropyl-2,3,6, 7-tetrahydro·1Η_嘌吟-8-yl)-5-methyl-^pyrim-1 -yl]-indole-(4-phenylphenyl)-ethanoamine, and 2-[4-iodine _3-(2,6-di-oxy-1,3-dipropyl-2,3,6,7-tetrahydro-1Η-嘌120857.doc -20- 200813056 °令_8-ylmethyl ^Bizozol-1-yl]-N-(4-phenylphenyl)-acetamide; or a pharmaceutically acceptable salt thereof. Compounds of formula (1) can be prepared using methods well known in the art or using methods of their modification, such as those outlined in Scheme 1 herein. Process 1:

As exemplified in Scheme 1, a compound can be prepared starting from a compound of formula (11) wherein it is converted to have a meaning as defined above and the scale represents a lower alkyl group, preferably a U methyl or ethyl group. a compound of formula (1) (wherein R1, R2, R3, R4, I and R6 have the meanings as defined above), that is, by using an alkylating agent of formula (III) wherein R5 and I have as defined above By definition, and X denotes a leaving group such as chloro, bromo, iodo, methanesulfonate or tosylate, to convert a compound of formula (Π) to a compound of formula (IV) Wherein ^^ has the meaning as defined above). Preferably, the test (such as a metal alkoxide, under the presence of an organic solvent such as methanol or ethanol) at room temperature (RT)

120857.doc -21 - 200813056 Compounds of formula (π) (wherein R, heart and heart have the meanings as defined above) are known, or if they are novel #', they are well known in the art. The method or its improved method is prepared. For example, a compound of the formula: 〇 can be obtained in a polar organic solvent (such as a lower alkyl alcohol such as EtOH) at a high temperature, preferably at the boiling point of the solvent or near the boiling point of the solvent.

Wherein R and R4 have the meanings as defined above, condensed with an onium salt to obtain a compound of formula (11) wherein & is hydrogen. Further, a halogenating agent (such as N-halo-succinimide, such as N-aluminum amber imine, N) may be used in the presence of a suitable organic solvent such as N,N-dimethylformamide (DMF). • Bromo-succinimide and N-iodosinimide) treatment of a compound of the formula (Π) wherein R3 is hydrogen is converted to the corresponding compound of formula (II) wherein & The reaction is preferably carried out at a temperature ranging from about 〇r to room temperature. Likewise, a compound of formula (III) wherein X, 1 and heart have the meanings as defined above, or if it is novel, may be as described in the exemplified examples herein, or used herein. The methods well known in the art or their improved methods are prepared. The compound of formula (IV) wherein R, Rr R4, 1 and 1 have the meanings as defined above is then hydrolyzed to give a compound of formula (V) wherein R 3 , R 4 , & and trans 6 have the meanings as defined above For example, it may be used in an organic solvent such as 120857.doc -22-200813056 tetrahydrofuran (THF) or diaceous (preferably dioxane) such as sodium bismuth oxide (NaOH) or hydrazine. Treatment of a compound of the formula (IV) with an aqueous solution of potassium oxide (K〇H) (wherein R is a lower alkyl group, such as a methyl or ethyl bromide hydrolysis step is preferably carried out at room temperature. a coupling agent of 3-ethyl-helium dimethylaminopropyl propyl)_3_ethylcarbodiimide hydrochloride (EDC1) or hydrazine, 3_dicyclohexylcarbodiimide (DCC) and a compound of the formula (v) wherein &, R4, Rs and R6 have the meanings as defined above, in the presence of a lower alkyl alcohol (preferably Me〇H or an organic solvent) Substituting · 5,6-diaminouracil (the centralization of which has the meaning as defined above) is coupled to give the intermediate amide derivative Substituting, which is then cyclized to obtain a compound of formula (1) (where Ri, R2, R3, via treatment with an aqueous base such as NaOH or KOH in an organic bath such as a lower alkyl alcohol (preferably Me〇H) R4, R5 and R0 have the meanings as defined above. The coupling reaction is preferably carried out at room temperature (RT) and the cyclization step is preferably carried out at a temperature ranging from about 5 Torr to about 80 °C. The method can be carried out under inert atmosphere, preferably under nitrogen atmosphere. In the manner described herein, it is converted into a starting compound and an intermediate of the compound of the present invention, and is used in the preparation of organic chemistry as appropriate. Knowing protecting groups to protect functional groups such as amine groups, thiols, carboxyl groups and hydroxyl groups. Protected amine groups, thiols, carboxyl groups and hydroxyl groups are mild without breaking the molecular framework or other undesirable side reactions. The functional group is converted to a free amine group, a thiol group, a carboxyl group and a hydroxyl group. 120857.doc -23- 200813056 The purpose of introducing a sulfhydryl group is to protect the functional group from reacting under the conditions used for the desired chemical conversion. Component does not occur The requirements and selection of the protecting group for a particular reaction are known to those skilled in the art, and depending on the nature of the functional group to be protected (hydroxyl, amine, etc.), the structure and stability of the molecule having a substituent moiety And the reaction conditions are well known. The well-known protecting groups which satisfy these conditions and their introduction and removal are described, for example, in McOmie, (Pr〇tective Gr〇ups in Organic Chemistry), Plenum Press, L〇nd〇n, Νγ (1973) and

Greene and Wuts,, 'Protective Groups in

Organic Synthesis)^, John Wiley and Sons, Inc. 5 NY (1999). The above-mentioned reactions are carried out according to standard methods in the presence or absence of a catalyst, a condensing agent or a diluent of each of the other reagents (preferably such as a solvent which is inert to the reagent and which is a reagent) and/or inert atmosphere. At low temperature, room temperature or elevated temperature, preferably at the boiling point of the solvent used or close to the boiling point of the solvent used and at atmospheric pressure or superatmospheric pressure. Preferred solvents, catalysts and reaction conditions are set forth in the accompanying illustrative examples. The invention further comprises any variant of the process according to the invention, wherein an intermediate product obtainable at any time thereof is used as starting material and the remaining step or wherein the starting material is formed in situ under the reaction conditions, or wherein the reaction component is used The salt form. The compound of the present invention and the intermediate may also be converted into each other according to a method generally known per se. The invention is also directed to any novel starting materials, intermediates, and processes thereof. 120857.doc -24- 200813056 Methods. Depending on the starting materials and methods, the novel compounds may be in the form of possible isomers or mixtures thereof, such as substantially pure geometric (cis or trans) isomers, diastereomers, optics. Isomer, racemate

Or a mixture thereof. The above possible isomers or mixtures thereof are within the scope. X Any resulting mixture of isomers may be based on physicochemical differences in the composition, for example by knife-step crystallization and/or layer #, for example by using a liquid chromatography (HPLC) with a palmitic adsorbent. It is isolated as a pure geometric isomer, a diastereomer. -" Finally, the compounds of the invention are obtained in free form or in the form of their salts, preferably in the form of their pharmaceutically acceptable salts. Specifically, the compound of the invention containing an assay group can be converted to an acid addition salt, especially a pharmaceutically acceptable acid addition salt. These salts are formed with, for example, mineral acids such as mineral acids, such as sulfuric acid, phosphoric acid or hydrogen dentate; or organic carboxylic acids such as, for example, unsubstituted or halogen-substituted qc:4 alkanoic acids. For example, acetic acid, such as a saturated or unsaturated dicarboxylic acid, such as oxalic acid, (tetra) acid, cis- enedienedioic acid or fumaric acid, such as carboxylic acid, such as glycolic acid, lactic acid, malic acid, tartaric acid or lactic acid 'such as an amino acid' such as aspartic acid or a face acid; "organic sulfonic acid, such as q-C4 alkyl sulfonic acid, such as methanesulfonic acid; or unsubstituted or substituted (for example, substituted by halogen) Base sulfonic acid. Preferred are salts formed with hydrochloric acid, maleic acid and sulfonic acid. The τ is advantageously formed into a salt using a conventional method in the presence of (d) or an alcoholic solvent such as a low carbon number alkanol. Ethers (eg, 120857.doc -25-200813056 such as B- or petroleum scales) may be used to treat the salt from such a suitable base (eg, a gas-based solution of a sulphate. It may be treated by (such as sodium ruthenium oxide). The salt can be used to purify the obtained compound. In view of the allowable or appropriate form of the free compound and the salt, the tangent of the human J is mentioned. Relationship, as long as ... k and the compound also means the corresponding salt. b (including its salt) can also be obtained in the form of other lysates for crystallization, or include

22: The compound of formula (1) can be labeled with any suitable radioactive label... an example package suitable for radiolabeling... Isotope (eg "C" but any non-toxic radiolabel commonly used for pharmacokinetic studies can also be used. The method of incorporating a radioactive standard on an organic compound is well known to those of ordinary skill. For example, 'a di-substituted 5'6-diamine-based urine (IV) of the formula (5) containing a suitable radioactive label can be obtained, for example. It is easy to obtain a 1'3-disubstituted-5,6-diaminouracil of formula (5), the center and the heart of which contain one or more sites of unsaturation. It can then be applied to a suitable catalyst (for example, charcoal or other In the presence of a hydrogenation catalyst, the unsaturated carbon-carbon double bond or the bond is reacted with hydrazine. The radiolabeled diamine-based urine (IV) is used and according to the & method as described above, followed by the corresponding Radiolabeled compounds of formula (I). It has been determined in the art that compounds labeled with 3Η and UC have a binding to the genotypes of agglutinin, A2a, octa (9) and a3 receptors comparable to the corresponding unlabeled forms. Dear And, therefore, the radiolabeled compound of formula (1) can be used as a radioligand for studying the biological activity associated with adenosine receptors (especially adenosine A2b 120857.doc -26-200813056 receptor). The compound of the present invention is a glandular a2B receptor antagonist. The present invention therefore provides a species for regulating adenoid A in a mammal.

The method of receptor activity is such that the method of formulating a human (2) compound comprises administering a therapeutically effective amount of a compound of formula (I) to a mammal in need thereof.

Furthermore, the compounds of formula (1) are useful in the treatment of conditions mediated by adenosine 2 receptors. Therefore, these compounds can be used therapeutically in the treatment of the following diseases: chronic and acute inflammatory diseases involving mast cell degranulation, such as asthma, allergic rhinitis and allergic dermatitis; abnormal sensitivity to insulin, such as type 2 diabetes , non-insulin-dependent diabetes mellitus, pre-diabetes state and glucose tolerance abnormalities; diseases with angiogenesis as a key cause of disease such as solid tumors and angiogenic retinopathy; premature infant apnea; myocardial reperfusion injury; Enteropathy; autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and lupus erythematosus; diseases involving retinal microvascular abnormalities mediated by adenine 2 Β receptors, such as retinopathy of prematurity, macular degeneration and diabetes Retinopathy; and heart disease, including hyperplasia caused by high blood pressure, arteriosclerosis and heart attack. In other words, the invention provides a method for treating a condition mediated by adenosine Am receptor comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention. "The term "treatment" encompasses or modally treats, and delays progression and mitigation as used throughout the specification and in the scope of the patent application, as well as all known forms known to those skilled in the art, including prophylactic treatment, curative treatment, Treatment. 120857.doc 27- 200813056 The term "therapeutically effective amount" as used herein refers to a desired biological or ubiquitous response that can trigger a tissue, system or animal (including humans) pursued by a researcher or clinician. The amount of the drug or therapeutic agent. The term "mammal" or "patient" is used interchangeably herein and includes, but is not limited to, humans, dogs, miscellaneous, horses, pigs, cows, sheep, monkeys. , rabbits, mice and laboratory animals. The preferred mammal is human. The method of local Ming is better for the treatment of asthma and diabetes.

Further, the present invention provides a method as defined above, which comprises: co-administering an effective amount of a compound of the formula (1) or a pharmaceutically acceptable salt thereof and a second drug 'the second drug' (for example, simultaneously or sequentially) For example, an anti-inflammatory, anti-diabetic or anti-hypertensive agent as described below. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, alone or in combination with - or a plurality of pharmaceutically acceptable carriers. The pharmaceutical composition according to the present invention is a medicine suitable for enteral (such as wart or rectal) 4, transdermal and parenteral administration to a mammal including humans for the treatment of a condition mediated by the gland A2B. combination. Such conditions include, but are not limited to, chronic and acute inflammatory diseases involving mast cell degranulation, such as asthma, allergic rhinitis and allergic dermatitis; abnormal sensitivity to insulin 'eg type 2 diabetes, non-Tengol-dependent Diabetes, pre-diabetes and glucose tolerance; diseases with angiogenesis as a key cause of disease, such as solid tumors and angiogenic rickets; premature infant apnea; myocardial reperfusion injury; inflammatory bowel disease Autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and lupus erythematosus; diseases involving retinal microvascular abnormalities mediated by adenosine Am receptors, such as retinopathy of prematurity, Macular degeneration and diabetic retinopathy; and heart disease, including hyperplasia caused by high blood pressure, arteriosclerosis and heart attack. Thus, the compounds of the present invention are useful in the manufacture of pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in association with or in admixture with an enteral or parenteral excipient or carrier. Preferred are tablets and gelatin capsules containing active ingredients: and the following: mannitol, sorbitol, or salt and/or salt

a) diluents such as lactose, dextrose, sucrose, cellulose and/or glycine: b) lubricants such as vermiculite, talc, stearic acid or polyethylene glycol; for tablets Also included is a) c) binder, such as magnesium sulphate, powder paste, gelatin, tragacanth, cellulose, (tetra) cellulose and/or polyethylene (4) money;

d) a disintegrant such as starch, turmeric, a mixture; and/or alginic acid or a sodium salt thereof, or foaming and a suppository advantageous e) an absorbent, a coloring agent, a flavoring agent and a sweetener. The composition for injection is preferably prepared as a (iv) aqueous solution or suspension from a fat emulsion or suspension. "etc." may be sterilized and/or contain adjuvants such as preservatives, wetting agents or emulsifiers "salts and/or buffers. In addition, a de-promoting agent and a substance for regulating the osmotic pressure are used. The compositions are separately delivered; they may also be prepared by other therapeutically valuable means. "糸 According to conventional mixing, granulating or coating methods 120857.doc -29- 200813056 In general, the concentration of the compound of the invention in a liquid composition such as a lotion will be from about 0.01 to 25 weights. Preferably, it is from about 01% to about 1% by weight. The concentration in the semi-solid or solid composition (such as a gel or powder) will range from about 〇·· to $% by weight, preferably from about 0·5 to 2·5 by weight. Formulations suitable for transdermal administration include a therapeutically effective amount of a compound of the present invention and a carrier. Advantageous carriers include a pharmaceutically acceptable pharmaceutically acceptable solvent for aiding penetration through the skin of the host. Characteristically in the form of a bandage comprising a substrate member, a reservoir containing a compound (as appropriate with a carrier), and a selectable rate control barrier (for delivering the compound to the host skin at a controlled and predetermined rate) For a longer period of time) and means for fixing the device to the skin. When used for the treatment of retinal vascular ischemic injury, it is preferred to formulate the compound of the present invention into an eye drop suitable for topical application. Self inhaler An insufflator, nebulizer or pressurized pack or other member that delivers an aerosol spray is inhaled to administer the compound of the invention. The pressurized pack may use a suitable propellant such as carbon dioxide or other suitable gas. In this case, the dosage unit can be determined by providing _ to deliver the metered amount. Inhalers, blowers and sprayers are well described in the medical reference book. 4 such as Remington, s bribery (4) This (5) Sciences 18 (199 〇) Mack publishing c〇, fine (10), 卜. The amount of the compound of the invention required for treatment will vary not only according to the particular salt selected, but also depending on the route of administration, the nature of the condition being treated and The patient's age and condition will vary and will ultimately be determined by the pharmacist or clinician. In general, the appropriate dose will range from about 〇天〇 to about 120857.doc -30- 200813056 20 mg/kg/day. For example, the dose may be from 〇〇〇2 mg/kg body weight to about 10 mg/kg body weight per day, preferably in the range of 〇〇i mg/kg/day to 1 mg/kg/day, and optimally in oj Range of mg/kg/day to 5 mg/kg/day Compound conveniently administered in unit dosage form, each unit dosage form for example containing 5 pg to 1000 pg, suitably 1〇 to 75〇 called nap, most suitably 50 pg to 500 pg of active ingredient.

U may suitably be administered in a single dose or in divided doses administered at appropriate intervals (e.g., two, three, four or more sub-doses per day) to provide the desired agent. The sub-dosing agent itself may be further divided into, for example, multiple discrete loosely spaced administrations, such as multiple inhalations from the insufflator or by applying a plurality of drops to the eye. Dosages above or below the ranges cited above are within the scope of the invention and can be administered to individual patients as needed and necessary. Accordingly, the present invention provides pharmaceutical compositions as described above for use in the treatment of a condition mediated by the adenine A2b receptor, including f- and sexually inflammatory diseases involving mast cell degranulation, such as asthma, allergies Rhinitis and atopic dermatitis; abnormalities in insulin sensitivity, such as type 2 diabetes, non-insulin-dependent diabetes mellitus, pre-diabetes status, and glucose tolerance, and diseases in which blood-burden formation is a key cause of disease, such as entities Tumors; blood-creative retinopathy; premature infant apnea; myocardial reperfusion injury, human f-intestinal disease, autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and lupus erythematosus; Glycoside-receptor-mediated diseases of retinal microvascular abnormalities, such as retinopathy of prematurity, macular degeneration and diabetic retinopathy; and heart disease, including increased by hypertension 120857.doc -31- 200813056 Health, arteriosclerosis heart attack. The (iv) composition may comprise a therapeutically effective amount of a compound of the invention as defined above, alone or in combination with another therapeutic agent, e.g., each of the effective therapeutic doses reported in the art. Such therapeutic agents include:

Inflammatory anti-inflammatory agents, such as anticholinergic or antimuscarinic agents, steroids, ltb4 (leukotriene B4) antagonists, methyleneamine receptor agonists, PDE4 (phosphodiesterase 4) inhibitors, and "adrenal glands Receptor agonist; b) anti-diabetic agents, such as insulin, 胄 Island (4) bio 1 mimetic; insulin secretagogue; insulinotropic sulphonylurea receptor ligand: smolderone derivative; GSK3 (liver Glyco synthase kinase 3) inhibitor; nano-dependent glucose co-transporter inhibitor; hepatic sugar-storing enzyme inhibitor; biguanide; alpha-glucosidase inhibitor; Gw] (glycin-like peptide <) , 〇1^] analogues and GLP-1 mimetic; ppAR (peroxisome proliferator-activated receptor) modulator, DPPIV (dipeptidyl peptidase IV) inhibits Qi; SCD] (stearyl sulfhydryl-coenzyme A desaturase-1) inhibitor; DGAT1 and DGAT2 (dimercaptoglycerol thiol transferase 1 and 2) inhibitors; ACC2 (acetamidine A carboxylase 2) inhibitor, and AGE (advanced glycosyl) End product; lysing agent; C) anti-office blood pressure agent such as loop diuretics; angiotensin-converting enzyme (ACE) inhibitor; Na-K-ATPase membrane Pump inhibitors such as digoxin; neutral endopeptidase (NEP) inhibitors; ACE/NEP inhibitors; angiotensin II antagonists; renin inhibitors beta-adrenergic receptors Blocker; myocardial contractant; calcium channel blocker 'juno-receptor antagonist; and aldosterone synthase inhibitor; and d) anti-lipid aberrant, such as 3-hydroxy-3-methyl-pentane Kiev enzyme 120857.doc -32- 200813056 A (HMG-CoA) reductase inhibitor; compounds that increase hdL, such as cholesterol ester transfer protein (CETP) inhibitor; squalene synthetase inhibitor; FXR (Fani _ ( Famesoid) X receptor) and LXR (liver X receptor) ligand; cholestyramine; fiber ester; niacin; and aspirin. As indicated above, the compounds of the invention may be administered separately or together with the other active ingredients, either before or after, by the same or different routes of administration, or together in the same pharmaceutical formulation.

I Accordingly, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a therapeutically effective amount of another therapeutic agent (preferably Fengbaijie, antidiabetic, antihypertensive, and anti-lipid aberrant) combination. Since the present invention has aspects associated with the use of a combination of compounds that can be co-administered separately, the present invention is also directed to combining individual pharmaceutical compositions in a kit format. The kit comprises two separate pharmaceutical compositions: (1) a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in addition to a pharmaceutically acceptable carrier or diluent; 2) A composition comprising an anti-inflammatory agent, an anti-diabetic agent, an anti-hypertensive agent or an anti-lipid alkalogue, or a pharmaceutically acceptable salt thereof, in addition to a pharmaceutically acceptable carrier or diluent. The amounts of (1) and (2) are those which, when administered alone, result in a beneficial therapeutic effect. The kit comprises a container for holding a separate composition, such as a separate vial or a separate fl package' wherein each compartment contains a plurality of (1) or (7) types (e.g., tablets). Alternatively, the kit may contain separate compartments, each containing a full dose comprising a separate dosage form, without separating the active ingredient two = type: one example of the set is a blister pack, wherein each individual bubble (or Two or more lozenges, one (or more) lozenges comprise the pharmaceutical composition 120857.doc-33-200813056 pharmaceutical composition (1) and the second (or more) lozenges comprise the pharmaceutical composition (2). Typically, the kit contains instructions for administering the individual components. When the individual group injury is preferably administered in different dosage forms (eg, oral and parenteral), at different intervals in the agent, or when the prescribing physician needs to titrate the individual group injury of the combination, the kit form Especially advantageous. In the context of the present invention, the kit thus comprises: (1) a therapeutically effective amount of a first dosage form comprising a compound of formula (1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent a composition of the second dosage form comprising an anti-inflammatory agent, an anti-diabetic agent, an antihypertensive agent or an anti-lipidal agent, or a pharmaceutically acceptable salt thereof, which is administered in the summer after administration to provide a beneficial therapeutic effect, And a pharmaceutically acceptable carrier or diluent composition; and (3) a container for the first and second dosage forms. The invention further relates to a pharmaceutical composition for use as a medicament as described above. The invention further relates to the use of a pharmaceutical combination as described above for the preparation of a medicament for the treatment of a condition mediated by the adenosine A1b receptor, including chronic and acute inflammatory diseases involving mast cell degranulation, For example, asthma, allergic rhinitis and allergic dermatitis; abnormal sensitivity to insulin, such as type 2 diabetes, non-insulin-dependent diabetes, pre-diabetic state and impaired glucose tolerance; diseases with angiogenesis as a key cause of disease, For example, solid tumors and angiogenic retinopathy; premature infant apnea; myocardial reperfusion injury; inflammatory bowel disease; autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and lupus erythematosus; involving 120857.doc -34- 200813056 Adeno-Am receptor-mediated diseases of the microvascular abnormalities, such as retinopathy of prematurity, macular degeneration and diabetic retinopathy; and heart disease, including hyperplasia caused by hypertension, arteriosclerosis and heart The onset of the disease. Accordingly, the present invention is also directed to the use of a compound of formula (1) for use as a medicament for the preparation of a pharmaceutical composition for the treatment of a condition mediated by adenosine Am receptors, and A pharmaceutical composition comprising a glucoside Am receptor mediated condition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier p. Finally, the invention provides a method or co-administration comprising administering a therapeutically effective amount of a compound of formula (I) in combination with an anti-inflammatory agent, an anti-diabetic agent, an anti-hypertensive agent or an anti-lipid aberrant. Finally, the invention provides a method or use comprising administering a compound of formula (1) in the form of a pharmaceutical composition as described herein. The above characteristics can be advantageously demonstrated in mammals (e.g., mice, rats, dogs, sheep, monkeys) or their isolated organs, tissues, and specimens in vitro and in vivo: in vivo tests. The compounds can be administered in the form of a solution (e.g., preferably an aqueous solution) in vitro, and enterally, parenterally, advantageously intravenously in vivo, for example, as a suspension or aqueous solution. The amount of the in vitro agent may be in the range of about 1 (Γ2 mole to 1〇-9 molar concentration. The therapeutically effective amount in vivo may be between about 0.001 mg/kg and 1000 Sg depending on the route of administration. Between about 0.01 mg/kg and 100 mg/kg, more preferably between about 0.1 mg/kg and 1 mg/kg. The activity of the compound according to the invention can be used in the art. A method of detailed description, such as the method described below, is evaluated. 120857.doc -35- 200813056 CHO membrane preparation according to the method previously described by Klotz et al. (Naunyn-Schmied. Arch Pharm 1998, 357: 1-9) The human adenosine receptor was transfected into CHO cells. Briefly, the cells were allowed to grow at 37 ° C in 5% CO 2 /95% air and maintained in Dubuy containing the nutrient mixture F12 without nucleosides. Dulbecco's Modified Eagles Medium (DMEM/F12) containing 10% fetal bovine serum, penicillin (100 U/mL), streptomycin (100 pg/mL), L-bran Amino acid (2 mM) and Geneticin (G4 18, 0.2 mg/ml). The medium was removed and the cells were washed with phosphate buffered saline and Ice-cold hypotonic buffer (5 mM Tris HC Bu 1 mM EDTA, pH 7.4) was scraped from the T75 flask for membrane preparation. The cell suspension was homogenized using a Polytron, and the tissue was homogenized in l〇〇. Spin at xg for 10 minutes, and then centrifuge the supernatant at 100,000 xg for 30 minutes. For the octa-adenosine receptor, centrifuge the membrane pellet in 50 mM Tris HCl buffer (pH 7.4) for A2A adenosine The receptor was suspended in 50 mM Tris HCb 10 mM MgCl2 (pH 7.4) and suspended in 50 mM Tris HC1, 10 mM MgCl2, 1 mM EDTA (pH 7.4) for A2b and A3 adenosine receptors. , A2A, A2B, and A3 Adenosine Receptor Binding Assays All newly synthesized compounds were tested for their affinity for human Ai, A2A, A2B, and A3 adenosine receptors. The diluted membrane was incubated at 25 °C (per Subsequent detection of 50 gg protein) with at least 6 to 8 different concentrations of the tested antagonist for [3H]-DPCPX replacement of CHO cells transfected with human recombinant octa-adenosine receptor for 120 minutes (Varani et al. Man, Mol. Pharmacol, 120857.doc -36- 200813056 2000, 57: 968-975). The non-specific binding was determined in the presence of 1 〇 μΜ CHA and it was always less than or equal to 1% of the total binding. At 4. Use a membrane suspension (50 pg protein per assay) with at least 6 to 8 different concentrations of the studied antagonist for 60 minutes of incubation time [3h]_zm 241385 and human recombinant Aw adenosine receptor transduction Binding of CHO cells stained. Non-specific binding was determined in the presence of 1 μΜ 241 385 and was about 20% of the total binding. The diluted membrane (50 pg protein per assay) was incubated with at least 6 to 8 different concentrations of the test compound for 12 min at 4 °C for [3h]-MRE 2029F20 and human recombinant a2R adenosine receptor Competition binding experiments of transfected CHO cells. Non-specific binding is defined as the binding in the presence of 1 μM MRE 3029F20 and is about 25% of the total binding. The diluted membrane (parent assay 50 pg protein) was incubated with at least 6 to 8 different concentrations of the tested ligand for 12 minutes at 4 ° C to carry out [3H]-MRE 3 008F20 on human recombinant As adenosine Competition binding assay of CHO cells transfected with Receptor 5. Non-specific binding is defined as the binding in the presence of 1 μΜ MRE 3008F20 and is about 25% of the total binding. The bound radioactivity and free radioactivity were separated by filtering the assay mixture via a Whatman GF/B glass fiber transition using a Micro-Mate 196 cell harvester (Packard Instrument Co.). The transitional radioactivity of the transition was counted on a Top Count (57% efficiency) with Micro-Scint 20. The amount of cyclic AMP in CHO cells transfected with human Αβ adenosine receptor was measured by phosphate-buffered physiological saline, diluted trypsin elution, and transfected with human A2B adenosine receptor. The cells were centrifuged at 200 g for 1 () minutes. Centrifuge blocks containing CHO cells (each assay ΐχ1()6 120857.doc -37-200813056 cells) were suspended in a 5 mL incubation mixture at 37 ° C: NaCl 1 50 mM, KC1 2·7 mM NaH2P04 0·37 mM, MgS〇4 1 mM, CaCl 2 1 mM, Hepes 5 mM, MgCl 2 l mM mM, glucose 5 mM, pH 7.4. Then add 2·0 IU/mL adenosine deaminase and 〇·5 mM as a phosphodiesterase inhibitor 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone ( R〇20_ 1724) and pre-incubated for 1 minute in a shaking tank at 37 °C. The potency of the antagonists studied was determined by antagonism of NECA (100 nM) induced stimulation of cyclic AMP levels. The reaction was terminated by the addition of cold 6% trichloroacetic acid (TCA). The TCA suspension was centrifuged at 2000 g for 10 minutes at 4 ° C, and the supernatant was extracted 4 times with water-saturated diethyl ether. The cyclic AMP content of the final aqueous solution was tested by competitive protein binding assay. A sample of the cyclic AMP standard (〇 to 10 pmol) was added to a incubation buffer containing a total volume of 〇·5 mL (Trizma base 0·1 Μ, amine theophylline 8.0 mM, 2-mercaptoethanol 6·0 mM ( pH 7.4)) and [3H] ring AMP in each tube. The binding protein previously prepared from the bovine adrenal gland was added to the sample previously incubated at 4 °C for a minute and centrifuged at 2000 g for 10 minutes after the addition of charcoal. The clarified supernatant was counted with 4 mL of Atomlight liquid scintillator and counted in a Tri Carb Packard 2500 TR scintillation counter. Data Analysis Protein concentration was determined using Bovine Albumin as a standard reference according to the Bio-Rad method (Bradford, Anal Biochem 1976, 72: 248-254). The inhibition binding constant was calculated from the IC5 enthalpy according to the Cheng & Prusoff equation (Biochem Pharmacol. 1973, 22: 3099-3 108).

Ki=IC5〇/(l + [C*]/KD*) 120857.doc -38 - 200813056 where [c*] is the concentration of the radioligand and kd* is its dissociation constant. Brain analysis of inhibition experiments was performed using a weighted nonlinear least squares curve fitting program LIGAND (Munson et al., Anal. Biochem. 1980, 107: 220-239). The data is represented as a geometric mean with a 95% confidence limit in parentheses. Examples of animal models The efficacy of the compounds of the invention in inhibiting an inflammatory condition, such as an inflammatory airway disease, can be demonstrated in a suitable animal model of bronchitis or other inflammation, such as a mouse or rat model, such as 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: 2924-293 1 ; and Cemadas et al, Am. J. Respir. Cell Mol. Biol. 1999, 20: 1-8. Preferably, the in vivo efficacy of the compounds of the invention is tested in sheep which are naturally sensitive to the allergen swine Swswm, for example, Abraham et al., Am. J. Respir. Crit. Care. Med. 2000, 162: 603-611 Fath et al., J. Biol. Chem. 1998, 273: 13563-13569; and Fujimoto et al., Eur. Respir. J. 1996, 9: 2044-2049. The in vivo efficacy of the compounds of the invention in the treatment of heart disease can be assessed in animal models well known in the art, for example by using apo-lipoprotein E knockout gene mouse model which has become one of the main models of atherosclerosis. (Arterioscler. Thromb. Vase. Biol. 2004, 24: 1006-1014; Trends Cardiovasc. Med. 2004, 14: 187-190). Such studies can be carried out as described by Johnson et al., Circulation 2005, 111: 1422-1430, 120857. doc-39-200813056, or using improved methods thereof. The in vivo glucose and insulin lowering activity of the compounds of the invention can be assessed as follows: 11-week old adult male C57BL ob/ob mice (Jackson Lab, Bar Harbor, ME) are placed in inverted light cycles of 6 per cage. Indoors (light from 6:00 pm to 6:00 am) and allow for free intake of Purina murine feed and water. The tail blood sample was taken at 8:00 am on the first day and the plasma glucose level was determined. Animals were randomly divided into control group and compound group. The plasma glucose values of these groups are closely related. Then Dong Xuan served more than iU you I, winter right 0 9 〇 / 〇

A 0.5% carboxymethylcellulose of Tween-80 or a test compound (e.g., 30 mg/kg) contained in a vehicle. The mice were administered per sputum for a total of 3 days. Baseline blood samples were taken on day 4. The glucose concentration of the plasma samples was analyzed using, for example, a YSI 2700 dual channel biochemical analyzer (Yellow Springs Instrument Co., Yellow Springs, OH) and the plasma samples were analyzed for insulin concentrations using an ELISA assay. In an illustrative embodiment of the invention, the compound of Example 4 exhibits an IC5 devaluation of about 43 nM in a functional assay for measuring cAMP content in CHO cells expressing the human adenosine A2B receptor. Further combinations and functional aspects of illustrative examples of the invention are provided in Table 1. 120857.doc -40· 200813056 Table 1: IC5〇(nM) hA2Be r

Example _ Ki(nM) No. hA!a hA2Ab hA3c hA2Bd 1 350 (275 to 482) Greater than 1000 Greater than 1000 15 (10 to 21) 2 Greater than 1000 Greater than 1000 Greater than 1000 28 (18 to 43) 3 Greater than 1000 Greater than 1000 Greater than 1000 35 (27 to 45) 4 greater than 1000) greater than 1000 greater than 1000 ^ 7.0 (5.34 to 9.06) 5 500 (420 to 595) greater than 1000 greater than 1000 14 (10 to 20) 6 greater than 1000 greater than 1000 greater than 1000 12 (8 to 18 7 Greater than 1000 Greater than 1000 Greater than 1000 48 (35 to 65) 8 Greater than 1000 Greater than 1000 Greater than 1000 60 (44 to 82) 9 Greater than 1000 Greater than 1000 Greater than 1000 Greater than 1000 10 140 (123 to 159) Greater than 1000 Greater than 1000 20 (15 To 26) 11 greater than 1000 greater than 1000) greater than 1000 greater than 1000 12 greater than 1000 greater than 1000) greater than 1000 greater than 1000 13 greater than 1000 greater than 1000 greater than 1000 greater than 1000 14 480 (444 to 518) greater than 1000 greater than 1000 65 (56 to 75) 15 675 (569 to 800) greater than 1000 greater than 1000 28 (19 to 41) 16 greater than 1000 greater than 1000 greater than 1000 40 (25 to 66) 17 greater than 1000 greater than 1000 greater than 1000 56 (45 to 70) 18 greater than 1000 greater than 1000 greater than 1000 222 (181 to 273) 19 is greater than 1000 1000 greater than 1000 250 (205 to 306) 20 greater than 1000 greater than 1000 greater than 1000 greater than 1000 58 (45 to 74) 115 (84 to 159) 156 (123198) 43 (31 to 60) 68 (51 to 91) 61 (44 to 84) 200 (182 to 219) 222 (203 to 242) Greater than 1000 80 (63 to 100) Greater than 1000 Greater than 1000 Greater than 1000 266 (216 to 327) 106 (81 to 139) 188 (166 to 213) 212 (162 to 277) greater than 1000 greater than 1000 greater than 1000 a specific for human A! receptors expressed in CHO cells [3h] replacement of DPCPX binding (n = 3 to 6). b The specificity of the human a2a receptor expressed in CHO cells [3H]ZM241385!i replacement (n=3 to 6). e is expressed in the specificity of the human a2B receptor in HEK293 cells [H] MRE2029F20 binding substitution (n = 3 to 6). d is expressed in the substitution of human A3 receptor specific [3H] MRE3008F20 binding in CHO cells (furnaces 3 to 6). e The cAMP assay was performed in CHO cells expressing the human A2b adenosine receptor. The binding and functional data are represented as Ki (nM) and IC5 〇 (nM), respectively. The experimental data is represented as a geometric mean with a confidence limit of 953⁄4. The examples disclosed herein are intended to be illustrative of the invention and are not to be considered as limiting. If not mentioned otherwise, all evaporation is carried out under (iv), preferably between about 10 mmHg and 100 mmHg. The structure of the final product, intermediate and starting materials is confirmed by standard analytical methods such as microanalysis, melting point (m.p.) and spectral characteristics such as MS, IR & NMR. Abbreviations used are abbreviations commonly known in the art. Example 1 2·[3·(2,6-di-oxy-indole, 3·dipropyl-2,3,6,7-tetrahydro-1H-decylmethyl-indazole-1·yl]-N _phenyl-acetonitrile

A·2-bromophenylacetamide is cooled on ice to a solution of aniline (〇·〇16 mol) in 40 mL of a two-gas methane, and 1 mL of methylene chloride in 3 mL of dichloromethane is added dropwise. Then, 0.019 mol of triethylamine (TEA) was added. As the reaction mixture was warmed to room temperature over 3 hours, the solution darkened and formed a precipitate. The mixture was concentrated and taken up in ethyl acetate (EtOAc) and washed three times with water. The organic phase was dried over anhydrous sodium sulfate (Na2SO4) filtered and concentrated. The residue was purified by crystallization from Et EtOAc to afford 2-bromo-p-phenylacetamide: m p. 131 to 135 ° C; iH-NMR (CDC13) δ 4·01 (s, 2H), 7.18 (m, 1H), 7·36 (m, 2Η), 7.54 (2Η), 8·09 (s, 1Η). Β·5_Methyl-i-phenylamine-mercaptomethyl-1H-pyrazole_3_carboxylic acid B. 120857.doc -42- 200813056 to 5-methyl-1H-pyrazole-3-carboxylic acid The title compound a 2-bromo-N-phenylacetamide (0.02 mol) was added to a mixture of the ester (0.02 m) and sodium ethoxide (0.22 mol) in ethanol (20 mL). The resulting suspension was stirred at room temperature for 3 hours. After concentration under vacuum, EtOAc was added and the obtained solution was washed twice with water and dried over anhydrous Naz SCU. After filtration and concentration, the residue was purified by flash chromatography (ethyl acetate / hexanes) to afford ethyl 5- decyl-1-phenylamine carbamide Mp· 139 to 140〇C; W-NIVIR (DMSO-d6) δ 1.26-1.29 (t,3H J=7.2 Hz), 2.28 (s,3H), 4.23-4.25 (q,2H J=7.2 Hz), 5.06 (s, 2H), 6.56 (s, 1H), 7.07 (m, 1H), 7·32 (m, 2H), 7.57 (m, 2H), 10.41 (s, 1H). C·5-Methyl-1-phenylamine-mercaptopurinylpyrimidinecarboxylic acid to the title B compound 5·methyl-1-phenylamine-mercapto-methyl-1H-pyridin-3-indole A 2 N aqueous KOH solution (5 mL) was added to a mixture of EtOAc (EtOAc) (EtOAc). After concentrating in vacuo, the residue was cooled and acidified with a 10% EtOAc solution to precipitate 5-methyl- s s s s s s s. D6) δ 2.28 (s, 3H), 5.06 (s, 2H), 6.56 (s, 1Η), 7.07 (m, 1Η), 7.32 (m, 2Η), 7·57 (m, 2Η), 10.41 (s, 1H), 12.50 (s, 1H). D· 2-[3·(2,6-di-oxy-i,3-dipropyl-2,3,6,7-tetrahydro·1Η_嘌呤·8-yl)-5-fluorenyl- Pyrazole-i• kibd-phenyl-acetamide to 1,3 propyl _5,6-monoaminouracil (2.20 mmol) in MeOH (1 〇120857.doc -43-200813056 mL Add the amount of the molar amount of the title compound c_5-methyl benzene f St* f S^^EDCI (2.21 mmol) 〇m The reaction mixture is stirred at room temperature for 4 to 5 hours while borrowing Supervised by TLC's J. In the real work, the solvent was condensed, and the indoleamine intermediate was won by adding water. After filtration, the solid was dissolved in MeOH (10 mL) and aqueous NaOH (2·5 N '15 mL), and the mixture was stirred for one hour & (Me) and the residue was dissolved. Acidified to pH 4 to 5 in H20 and with HCl. The precipitate was collected by filtration, washed with water and purified by flash chromatography (ethyl acetate EtOAc) to afford 2-[3-(2,6-di- oxy-1,3- propyl _ 2,3,6,7-tetrahydro-111-fluoren-8-yl)-5-methyl-pyrazol-1-yl]-phenylene acetamidine: mp·255 to 257. 〇;111_>^11(]〇]^8〇- d6) δ 0·87 (m,6H), 1.56 (q,2H), 1.70 (q,2H), 2.32 (s,3H), 3·84 (m, 2H), 3.98 (m, 2H), 5.08 (s, 2H), 6.74 (s, 1H), 7.08 O, 1H), 7.33 (m, 2H), 7.59 (m, 2H), 10.41 (s , 1H), 13.85 (s5 1H) 〇 Example 2 2-[3-(2,6-di- oxy-1,3-dipropyl-2,3,6,7_tetra argon_111_嘌呤- 8-yl)_5-methyl-pyrazole-yl b. ('Iodophenylacetamide Ο 类似于 The title compound was prepared in analogy to Example 1: mp 286 to 289. 〇; 111-NMR (DMS 〇-d6) δ 0.87 (m,6H),1.56 (q,2H),1.71 (q,2H), 120857.doc -44· 200813056 2·3〇(s5 3Η),3·84 ( ^lH), 7.42 (d 2Η: } 97 (t,2Η)>5·°7 (S} m 6·74 (s, 吼(10)('s,!V;; 8.8 Hz), 7.66 (d, 2Hj=8.8Hz), 10.52 Example 3 2-[3-(2,6_II-side gas _,3_dipropyl-2,3,6,7-tetrahydroindole-8-yl)-5•methyl olfactory 基] Ν布Ν·( 4_Bromophenyl)acetamide ί 1 Η Similar to the example 丨掣 supply, threat compound ··ρ· 270 to 273°c; NMR (DMSO-dJ “. 〇〇·87 (m, 6H ), L56 (q, 2H), 1.70 (q, 2H), 2.31 (s5 3H) 5 3.85 ( , m, 2H), 3.98 (m, 2H), 5.08 (s, 2H), 6.75 (s, 1H), 7.51 (d, 2ji w J=8.〇Hz), 7.57 (d, 2H J = 8.0 Hz) 5 10.56 (s, 1H), 13.69 (S, 1H). Example 4 2-[3-(2,6_two-side gas, its nine 丞-1,3_dipropyl_2,3, 6,7-Tetra-Arden_1H_嘌呤-8-yl)·5-fluorenylpyranylphenyl)-acetamide.Cl 类似于 Similar to the compound of Example 1 and mp 261 to 265. (:;111· NMR (DMSO^d6) a π 0 2m . ^ ^ 〇.87 (m,6H),1.56 (q,2H ), 1.70 (q, 2H),2·31 (s,3H) • 82 (ni, 2H), 3.95 (m, 2H), 5.07 (s, 2H), 120857.doc -45 - 200813056 6.73 (s, 1H), 7.37 (d, 2H J = 8.2 Hz), 7· 60 (d, 2H J = 8.2 Hz), 10.55 (s, 1H), 13.68 (s, 1H). Example 5 2-[3·(2,6·Di-Ethoxy-1,3dipropyl-2,3,6,7-tetrazo-111_嗓吟-8 yl)-5-methyl- Oxazol-1-yl]-N-(4-fluorophenyl)-acetamide

F The title compound was prepared in a similar manner to Example 1: mp 205 to 207 (3; 111-NMR (DMSO-d6) δ 0_87 (m, 6H), 1.56 (q5 2H), 1.70 (q, 2H), 2.31 (s5 3H ), 3.84 (t, 2H), 3.97 (t, 2H), 5_07 (s, 2H), 6.74 (s, 1H), 7.17 (d, 2H J = 8.8 Hz), 7.61 (d, 2H J = 8.8 Hz), 10.48 (s, 1H), 13.80 (s, 1H) 〇 Example 6 2-[3_(2,6_Di-Ethoxy-1,3-dipropyl-2,3,6,7-tetra Hydrogen-1H-嘌呤-8-yl)_5_methyl-η-pyrazol-1-yl]-anthracene (4-methoxyphenyl)-acetamide

The title compound was prepared in a similar manner to Example 1: mp. 293 S 296 ° C; 1H-NMR (DMSO-d6) δ 0_87 (m, 6H), 1.56 (q, 2H), 1.70 (q, 2H), 2.31 (s, 3H),3·71 (s,3H),3.84 (t,2H),3·97 (t,3H),5.03 120857.doc -46- 200813056 (s,2H),6.72 (s,1H),7.90 (d, 2H J = 8.2 Hz), 7.49 (d, 2H J = 8.2 Hz), 10.28 (s5 1H), 13.80 (s, 1H). Example 7 2-[3-(2,6-Di-Ethoxy-1,3-dipropyl-2,3,6,7-tetrazo-1Η-嗓吟-8 yl)-5-methyl- Zin-1-yl]·Ν-(3,4-dimethylphenyl)-acetamide

The title compound was prepared in a similar manner to Example 1 mp. 261 to 265. 111-NMR (DMSO-d6) δ 0.87 (m, 6H), 1.56 (q, 2H), 1·70 (q, 2H), 2.17 ( m,6H),2·31 (s,3H),3.84 (t,2H),3.97 (t,2H),5.03 (s,2H),6.70 (s,1H),7.06 (d,1H),7.29 (d, 1H), 7.37 (s, 1H), 10.24 (s, 1H), 13.80 (s, 1H). Example 8 2-[3_(2,6-Di-Ethoxy-1,3-dipropyl-2,3,6,7-tetrahydro-1H-indol-8-yl)-5-methylpyrazole -i_yl]_N-(3,4-dimethoxyphenyl)-acetamide

The title compound was prepared in a similar manner to Example 1. mp 285 S 290 ° C; 1H-NMR (DMSO-d6) δ 0.88 (m, 6H),1·57 (q5 2H),1·70 (q, 2H), 2 · 32 (s5 3Η), 3.71 (s, 6Η), 3.84 (t, 2Η), 3.88 (t, 2Η), 5·03 120857.doc -47- 200813056 (s, 2H), 6.73 (s, 1H), 6.90 (d, 1H), 7.05 (d, 1H), 7.32 (s, 1H), 10.29 (s, 1H), 13.88 (s, 1H). Example 9 2-[3-(2,6-Di-Sideoxy-1,3-dipropyl-2,3,6,7-tetrahydro-111-fluoren-8-yl)-5-ethyl-anthracene Oxazol-1_yl]_N-(4-hydrophenyl)acetamide

The title compound was prepared in a similar manner to Example 1: mp· 256 S 257°C; 1H·NMR (DMSO-d6) δ 0·88 (m, 6H), 1.25 (m, 3 Η), 1·55 (q, 2H), 1·70 (q, 2H), 2.66 (q, 2H), 3.84 (t, 2H), 3.99 (t, 2H), 5.08 (s5 2H), 6.77 (s, 1H), 7_40 (d, 2H J= 7.6 Hz ), 7.63 (d, 2H J=8.2 Hz), 10.56 (s, 1H), 13.67 (s, 1H). Example 10 2-[3-(2,6-Di-Ethyloxy-1,3-dipropyl-2,3,6,7-tetrazo-111-fluoren-8-yl)-. Bizozole-1·yl]-N-(4-phenylphenyl)acetamide

The title compound was prepared in a similar manner to Example 1: mp· 283 s 285°C; 1H· NMR (DMSO-d6) δ 0.87 (m, 6H),1·52 (q5 2H), 1.66 (q5 2H), 3.85 (t, 2H), 3.98 (t, 2H), 5.14 (s, 2H), 6.94 (d, 1H J = 2.4 120857.doc -48- 200813056 Ηζ), 7·37 (d, 2H J=8.8 Ηζ), 7· 60 (d, 2H J = 8.8 Hz ), 7.89 (d, 1H J = 2.6 Hz), 10.57 (s, 1H), 13.69 (s, 1H). Example 11 2-[3-(2,6-Di-Ethoxy-1,3-dipropyl-2,3,6,7-tetranitro-1H-indol-8-yl)-5-methyl-oxime Zin-1-yl]-N-(4-dimethylaminophenyl)-acetamide

The title compound was prepared in a similar manner to Example 1: mp > 300 ° C; h-NMR (DMSO-d6) δ 0·88 (m, 6H), 1.56 (q, 2H), 1.70 (q, 2H), 2.31 (s ,3H),2.84 (s,6H), 3·85 (t,2H), 3.94 (t,2H),5.01 (s, 2H),6.67 (s,1H),6.72 (d,2H J=9 Hz ), 7.42 (d, 2H J = 9 Hz), 10.11 (s, 1H), 13.70 (s, 1H). Example 12

2-[3_(2,6-di- oxy-1,3-dipropyl-2,3,6,7-tetrahydro-111-fluoren-8-yl)-5-methyl-11 ratio -1 _yl]-N-(4-second butylphenyl)-ethonamide

The title compound was prepared in a similar manner to Example 1: mp 268 SSTrC; 1!!-NMR DMSO-d6 δ 0.74 (t5 3H); 0.88 (m5 6H); 1.15 (q? 3H); 1.48-1.55 (m, 7H); (s,3H); 3.85 (t,2H); 3.97 (t,2H); 120857.doc -49- 200813056 5.06 (s5 2H); 6.74 (s5 1H); 7.14 (d5 2H); 7.49 (d5 2H) ; 10.33 (s, 1H); 13.75 (s, 1H). Example 13 2·[3_(2,6·di-oxy-1,3-dipropyl-2,3,6,7-tetrazo-1Η·嗓吟-8-yl)-5-fluorenyl-. Bizozol-1-yl](naphthalen-1-yl)-acetamide

The title compound was prepared in analogy to Example 1: mp > 300 ° C; h-NMR (DMSO-d6) δ 0·89 (m, 6H), 1.59 (q, 2H), 1·72 (q, 2H), 2 · 36 (s, 3H), 3.85 (t, 2H), 3.97 (t, 2H), 5.30 (s, 2H), 6.76 (s, 1H), 7.46-7.81 (m, 5H), 7.93-78.19 (m, 2H), 10.36 (s, 1H), 13.72 (s, 1H). Example 14 2-[3_(2,6-Di-Ethylene-1,3-dipropyl-2,3,6,7·tetrazine 1H-indol-8-yl)-5·decyl-α ratio Azole·1-yl]-N-(3-methoxyphenyl)-acetamide

The title compound was prepared in a similar manner to Example 1: mp 274 to s.: NMR (DMSO-d6) δ 0.87 (m, 6H), 1.58 (q, 2H), 1.68 (q, 2H), 2.31 ( s,3H),3.71 (s,3H),3.84 (t,3H),3.97 (t,2H),5.06 120857.doc -50- 200813056 (s,2H),6.63-6.68 (m,1Η),6 · 72 (s, 1H), 7.08-7.31 (m, 3H), 10.48 (s, 1H), 13.80 (s, 1H). Example 15 2-[3-(2,6-Di-Ethoxy-1,3-dipropyl-2,3,6,7-tetrahydro-111-fluoren-8-yl)-5-methyl- Carbazole-1-yl]-N-(3-phenylphenyl)-acetamide

The title compound was prepared in a similar manner to Example 1: mp·304 s 307°C; 1H-NMR (DMSO-d6) δ 0.87 (m, 6H), 1.56 (q, 2H), 1.70 (q, 2H), 2.31 (s, 3H), 3.84 (t, 2H), 3.95 (t, 2H), 5.09 (s, 2H), 6.73 (s, 1H), 7.15-7.80 (m, 4H), 10.48 (s, 1H), 13.80 (s5 1H). Example 16 2-[3-(2,6-di- oxy-1,3-dipropyl-2,3,6,7·tetranitro-1H- 嗓吟-8-yl)·5-methyl·pyrene Zin-1-yl]·Ν-(3,4-diphenyl)-acetamide

U The title compound was prepared in analogy to Example 1: m,p. 298 ° C; b-NMR (DMSO-d6) δ 0.87 (m, 6H), 1.57 (q, 2H), 1.73 (q, 2H), 2_31 (s ,3H),3.86 (t,2H),3·95 (t,2H),5.01 (s5 2H),6·75 (s, 1H), 7.47-7.59 (m,2H),7.97 (d,1H) , 10.73 (s, 1H), 13.75 120857.doc -51 - 200813056 (S, 1H) 〇 Example 17 pours dipropyl 2,3,6,7-tetrahydro-1H_嗓呤-8_ group) _5"Methyl" is more than olfactory base

: mp > 300 ° C ; ^-NMR compound similar to the example 1 锖 ( (DMSCUd6) δ 〇 · 88 (m3 6H), 157 (q, 2H), 1.72 (q, 2H), 2.25 (s, 3H), 2.31 (s, 3η), 3 μ (1) 2H), 3 99 (t, 2H), 5 〇 5 (s, 2H), 6.73 (s, 1H), 7 2 〇 8 Hz), 7.46 (d , 2H J=8.8

Hz)? 10.32 (s ’ V, 1H), 13.85 (bs, 1H). Example 18

2-[4_ gas-3·(2,6-di-sided oxyel,3-dipropyl-2,3,6,7-tetra-argon-1-indene·8-yl)·5-methyl _ Carbazole q•yl]_ν_(4_fluorophenyl)_acetamidamine

Α· 4-gas _5-methyl- than ____ formic acid ethyl vinegar (4 at 〇 ° C to 5-mercapto-1 Η · π Λ, _3 ethyl formate (3 mm 〇 l) at 1 〇 Add Ν·chloroammonium iminoamine to the magnetically stirred solution in mL water DMF. Stir the solution at room temperature for 5 hours. Concentrate the solvent to the original volume of 120857.doc -52- 200813056, add water and make the reaction mixture Cool on ice. The precipitated solid was collected by hydrazine and purified by crystallization to give a 4-yel-5-methyl-1H- s ratio as a white solid. Ethylene-3-carboxylate: ιη·ρ· 106 to 107 ° C; H-NMR (DMSO_d6) δ 1·25_1·32 (t5 3H J=7 Hz), 2.21 (s, 3H), 4.22-4.32 ( q, 2H J = 7.2), 13.59 (s, 1H). Β· 4_Gas_1-[(4_Gas-Phenylaminomethyl)methyl bromide 5_methyljjjj is prepared as the title b compound as described in the title B compound of Example 1 : mp 208 to 21 〇 ° C : W-NMR (DMSO-d6) δ 1.26-1.29 (t; 3H J = 7.2 Hz), 2.25 (s, 3H), 4.26-4.28 (q, 2IJ J = 7.2 Hz) , 5.14 (s, 2H), 7.39 (d, 2H J = 8.8 Hz), 7·60 (d, 2H J = 8.8 Hz), 10.60 (s, 1H) 〇C· 4-gas_1_[(4_ Gas, phenylamine, mercapto)-methyl]-5-methyl-1H-pyrazolic acid The title compound was prepared as described in the title compound of Example 1: mp 244 to 245 ° C; W-NMR ( DMSO-d6) δ 2.24 (s, 3H), 5·11 (s, 2Η), 7·39 (d, 2Η J=8.8 Ηζ), 7.60 (d 2Η J=8.8 Ηζ), 10·60 (s, !Η), 12.98 (s, 1Η). D· 2_[4_氱-3-(2,6-di- oxy-1,3-dipropyl-2,3,6,7_tetraar-1H_ 嘌呤-8-yl)-5·methyl -°Bizozol-1-yl]_N-(4-phenylphenyl)-acetamide The title compound was prepared as described in the title compound of Example 1: mp 297 to 298 ° C; iH-NMR (DMSO- D6) δ 0.88 (m, 6H), 1.62 (q, 2H), 1·70 (q, 2H), 2.31 (s, 3H), 3.8e (t, 2H), 4.00 (t5 2H), 5·! 5 (s5 2H), 7.39 (d, 2H J = 9 Hz), 7.61 (d, 2H J = 9 Hz), 120857.doc -53- 200813056 10.59 (s, 1H), 13.89 (s5 1H) 〇 Example 19 2-[4-Bromo-3·(2,6-di-oxo-oxime, 3·dipropyl-2,3,6,7-tetrahydro-1H-threo-8-yl)-5- Methyl-pyrazole-l-yl]-N-(4-phenylphenyl)-acetamide

The title compound was prepared in analogy to Example 18: m.p. 298 to 299. 〇;1!^· NMR (DMSO-d6) δ 0.88 (m, 6H), 1.57 (q, 2H), 1.72 (q, 2H), 2.321 (s, 3H), 3.91 (t, 2H), 4.02 ( t, 2H), 5.19 (s, 2H), 7.39 (d, 2H J = 9 Hz), 7.61 (d, 2H Hz), 10.68 (s, 1H), 13.79 (s, 1H). Example 20 2-[4-Iodine_3_(2,6-di-oxyl-1,3-dipropyl-2,3,6,7-tetrahydro-111-fluorenyl)_5·methyl·pyridyl Oxazole·1-yl]-N-(4-phenylphenyl)-acetamide

The title compound was prepared in analogy to Example 18: mp· 296 to 29 rc; ι Η NMR (DMSO d6) δ 〇·9 〇 (m, 6H), i 59 (+ 2H), i 74 (q, 2H), (s5 3H) , 3.87 (t5 2H)3 4.03 (t5 2H)5 5.19 (s5 2H)5 7.40 (d5 2H J=9 Hz) 7 c〇, t ' ·59 (d,2H J=9 Hz ), 10.58 (s, 1H), 13.87 (s5 1H) 〇120857.doc 54-

Claims (1)

200813056 X. Patent application scope: 1. A compound of the following formula Wherein Ri and R2 are each independently a Cl_C6 alkyl group, which may be optionally substituted: Cl~C4 alkoxy, cycloalkyl, c2-c4, I, G-C4 alkynyl or, optionally, up to 3 Monocyclic aryl groups substituted with substituents of the following groups of groups: CrC4 alkyl, = fluoromethyl, decyl, hydroxy, Cl_C4 alkoxy, methylenedioxy, thiol, CrCA thio , an aryl group, _, ei_e4_^ group, C^-C: 4 alkylthio group or c丨-C4 alkyl group; R3 is gas or _; and R5 is independently hydrogen or (^- (: 4 alkyl; R6 is aryl or heteroaryl, each of which may optionally be substituted with 1 to 3 substituents selected from the group consisting of: Cl-c6 alkyl, trimethylmethyl, C3_C : 6 cycloalkyl, halo, hydroxy, CVC6 alkoxy, methylenedioxy, ethylenedioxy, (^-(^ alkanoyl, Cr C6 decyloxy, c6-C1() aryl Oxyl, amine, CVC6 alkylamino, bis(Ci-C6 alkyl)amine, thiol, cvc6 alkylthio, C6_c1()arylthio, nitro, cyano, carboxyl, Cl- C6 alkoxycarbonyl, amine mercapto, alkylthiocarbonyl, alkyl sulfone 120857.doc 200 813056 Acidic or cvc1()arylsulfonyl; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein R3 is hydrogen; or a pharmaceutically acceptable salt thereof. The compound of claim 2, wherein R5 is hydrogen; and R6 is a monocyclic aryl group optionally substituted with 1 to 3 substituents selected from the group consisting of Ci_c6 alkyl, trifluoromethyl, C3_c: 6-rings, halo, hydroxy, Cl_c6 alkoxy, methylenedioxy, ethylenedioxy, Cl-C0 alkyl decyl, Cl_c6 alkoxy, C6_C10 aryloxy, amine, hydrazine 1-(:6-alkylamino group, bis(Cl-C6 alkyl)amino group, thiol, Cl_C6 alkylthio group, c6_Ci()arylthio group, nitro group, cyano group, carboxyl group, Cl-C6 alkane An oxycarbonyl group, an amine mercapto group, a CVC6 alkylthiocarbonyl group, a Cl_c6 alkylsulfonyl group or a c6_c10 aryl fluorenyl group; or a pharmaceutically acceptable salt thereof. 4. The compound of claim 3, Wherein Ri and Han 2 are, independently of each other, a Cl_c3 alkyl group optionally substituted by cyclopropyl, _CH=CH2, _C=CH or phenyl; or a pharmaceutically acceptable salt thereof. 5. The combination of claim 4 Wherein R4 is methyl; or a pharmaceutically acceptable salt thereof. 120857.doc 200813056 6. The compound of claim 1 which is selected from the group consisting of: 2·[3-(2,6 - Bis-oxy-1,3-dipropyl-2,3,6,7-tetrahydro-1Η-嘌呤-8-yl)-5-methyl-pyrazol-1-yl]-indole-benzene 2-ethylamine; 2-[3-(2,6·di-oxy-1,3-1,3-dipropyl-2,3,6,7-tetrahydro-1H-indol-8-yl)-5 Methyl-° ratio σ-l-yl]-N-(4-phenyl)-ethinamide, 2-[3-(2,6-di-oxy-1,3-dipropyl-2 ,3,6,7-tetrazo-111-嗓吟-8-yl)-5-methyl-oxazol-1-yl]-indole-(4-bromophenyl)acetamide; 2-[3_ (2,6-di-oxy-1,3-dipropyl-2,3,6,7-tetrahydro-1Η-嘌呤-8-篡V5-甲某-pyridin-1-篡1-Ν -Γ4-gas filled with a certain V-acetamide; __ / V - — ___ J \ V a / — ~' 2-[3-(2,6-di- oxy-1,3-dipropyl-2, 3,6,7_tetrahydro-1H-indol-8-yl)-5-methyl-oxazol-1-yl]·Ν-(4-fluorophenyl)-acetamide; 2-[3-( 2,6-di-oxyl-1,3·dipropyl-2,3,6,7-tetrahydro-1Η·嘌呤-8-yl)-5-methyl-n-pyrazol-1-yl] -Ν-(4-methoxyphenyl)-acetamide; 2-[3-(2,6 - Bis-oxy-1,3-dipropyl-2,3,6,7-tetrahydro-1Η-嘌呤-8-yl)-5-methyl-pyrazol-1-yl]-indole-( 3,4-dimercaptophenyl)·acetamidine; 2-[3-(2,6-di-oxy-1,3-dipropyl-2,3,6,7-tetrahydro-1Η -嘌呤-8-yl)-5-methylpyrazol-1-yl]-indole-(3,4-dimethoxyphenyl)-acetamide; 2-[3-(2,6-di Sideoxy-1,3_dipropyl-2,3,6,7-tetrahydro-111-嘌呤-8-yl)-5•ethyl-11 than β-spin-1-yl]_Ν-(4 - gas phenyl) ethylamine, 2-[3_(2,6-di-oxy-1,3-dipropyl-2,3,6,7-tetrahydro-111-fluoren-8-yl) -σ ratio ° sitting -1 -yl]·Ν-(4-phenylphenyl)-ethanoamine, 2_[3-(2,6-di-oxy-1,3·dipropyl-2,3 ,6,7-tetrahydro-1Η-嘌呤-8-yl)-5-methyl-° 吐-1 -yl]-Ν-(4-dimethylaminophenyl)-ethyl broth 120857.doc 200813056 amine; [(2,6_one-oxy-1,3-dipropyl-2,3,6,7-tetrahydro-1H-indene-soil) methyl-to-salt small base; |_N -(4-t-butylphenyl)-acetamidine; [3 (2,6·-o-oxy-1,3·dipropyl-2,3,6,7-tetrahydro-1H-indole- )5-methyl "bazole small group], naphthalene small group) acetaminophen; [3 (2'6-one oxy], 3_dipropyl·2,3,6,7-tetrahydro]indole-8)5-methyl ♦ sit small base] also (3 methoxy Ethylphenyl)-ethylamine; h[3_(2,6-di-oxy), dipropyl-2,3,6,7-tetrazinium,zirconazole^-'ylchlorophenyl Indoleamine; [3 (2'6_oneoxy-1,3-dipropyl-2,3,6,7-tetrahydro-1ΗΗ-yl-yl-methyl) "salt small base"*( 3,4-dichlorophenyl)-ethinamine; [(2'6-one oxy], 3-dipropyl-2,3,6,7-tetrahydro-1Η_嘌呤-cardiac) -5^Methyl "p-quinone-based" hepta-p-tolylamine; fish/gas 3 gas 2,6·di- oxy-1,3-dipropyl stomach 2,3,6,7- Tetrahydro-1Η-soil)5-methyl-pyrazole-yl]_Ν·(4_gasphenyl)_acetamide; Han_3-(2,6-di-oxy-1,3-di Propyl-2,3,6,7-tetrahydro·1Η-mouth 吟-8-yl)_ 5 - ψ a nix ^ 〇 sitting]*"基]-Ν·(4-gas phenyl)- Ethylamine; and: human [4'_3β (2, bis-oxo oxime 3-dipropyl., 3,6,7-tetrahydro-indole _ ...-8-yl)_5-methyl "pyrazole Small base]·ν♦chlorophenyl)-acetamide; or a pharmaceutically acceptable salt thereof. 7. A pharmaceutical composition comprising a therapeutically effective amount as claimed The combination of the substance and one or more pharmaceutically acceptable carriers. The pharmaceutical composition according to claim 7, which is for treating an inflammatory disease involving mast cell degranulation, involving insulin Symptoms of abnormal sensitivity 120857.doc 200813056 Diseases with angiogenesis as a key cause of disease, premature infant respiratory susceptibility ~ muscle reperfusion injury, inflammatory bowel disease, autoimmune disease, diseases involving retinal microvascular abnormalities and 9. The pharmaceutical composition according to claim 8, wherein the inflammatory disease involving mast cell degranulation is selected from the group consisting of asthma, allergic rhinitis and atopic dermatitis. 10. The pharmaceutical combination according to claim 8. The subject, wherein the condition involving abnormal sensitivity to insulin is selected from the group consisting of type 2 diabetes, a non-insulin-dependent glyco-g-diabetes state, and glucose and f-acceptance abnormalities. A composition wherein the disease in which angiogenesis is a key cause of disease is selected from the group consisting of a solid tumor and an angiogenic retinopathy. The pharmaceutical composition according to Item 8, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, and lupus erythematosus. The pharmaceutical composition according to claim 8, wherein the microvascular abnormality of the retina is involved The disease is selected from the group consisting of retinopathy of prematurity, macular degeneration, and diabetic retinopathy. The pharmaceutical composition of claim 8, wherein the heart disease is selected from the group consisting of hypertension, heart attack, and arteries. A group of hardened components. 1 5. The pharmaceutical composition of claim 7 for use in the treatment of asthma and diabetes. 16. The pharmaceutical composition of claim 7, which is for use as a medicament. 17. The use of a pharmaceutical composition according to claim 7 for the preparation of a medicament for the treatment of a condition mediated by Azb receptor activity by 120857.doc 200813056. 1 8. Use of a compound as claimed in the present invention for the preparation of a pharmaceutical composition for treating a condition mediated by Αα fork body activity. 19. The use of claim 17 or 18, wherein the condition mediated by octa (3) receptor activity is selected from the group consisting of an inflammatory disease of the sputum, a condition involving abnormal sensitivity to insulin, and a key cause of angiogenesis. Disease, premature apnea, myocardial reperfusion injury, inflammatory bowel disease, autoimmune disease, diseases involving retinal microvascular abnormalities, and heart disease. 20. The use of claim 19, which involves hypertrophy The inflammatory disease of cell degranulation is selected from the group consisting of asthma, allergic rhinitis and atopic dermatitis. 21. 22. / I. / The use of claim 19, wherein the condition involves an abnormal sensitivity to mesin The group is selected from the group consisting of type 2 diabetes, non-insulin-dependent diabetes mellitus, pre-diabetes state, and glucose tolerance abnormality. The use of the item 19, wherein the angiogenesis is a key factor causing disease is selected from an entity. A group consisting of a tumor and an angiogenic retinopathy. The use of claim 19, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis A group consisting of multiple sclerosis and lupus erythematosus. 24. The use of the subject 19, wherein the disease involving retinal microvascular abnormalities is selected from the group consisting of retinopathy of prematurity, macular degeneration, and diabetic retinopathy. The use of claim 19, wherein the heart disease is selected from the group consisting of hypertension, heart attack, and arteriosclerosis caused by hypertension. 120857.doc 200813056 26. The use of claim 17 or 18, wherein the A2B The subject mediated by the receptor activity is selected from the group consisting of asthma and diabetes. 27. The compound of claim 1 is used as a medicament. 120857.doc 200813056 VII. Designated representative map (1) Representative representative map of the case For: (none) (2) The symbol of the symbol of this representative figure is simple: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: (1) U 120857.doc