HK1148518B

HK1148518B - Substituted 8-heteroaryl xanthines

Info

Publication number: HK1148518B
Application number: HK11102551.4A
Authority: HK
Inventors: Wang Guoquan; M. Rieger Jayson; D. Thompson Robert
Original assignee: Allergan Sales, Llc
Priority date: 2003-08-25
Filing date: 2011-03-14
Publication date: 2012-12-21

Description

Substituted 8-heteroaryl xanthines

The present application is a divisional application of the invention patent application of PCT/US2004/027133 entitled "substituted 8-heteroaryl xanthines" filed on 8/20/2004 as the filing date, and the original application is Chinese patent application No. 200480031455.4.

Technical Field

The invention relates to a_2BCompounds and pharmaceutical compositions that are selective antagonists of Adenosine Receptors (ARs). These compounds and compositions are useful as medicaments.

Background

Alkylxanthine theophylline (1, 3-dimethylxanthine) (Compound A)

Is a weak, non-selective adenosine antagonist (see Linden, j. et al, ediovascularbiology of Purines, g. burnstock et al, eds., 1988, pages 1-20) that is therapeutically useful in the treatment of asthma. However, its use is associated with various unpleasant side effects, such as insomnia and polyuria. In recent years, the use of theophylline as a bronchodilator for the relief of asthma has been replaced by other classes of drugs, namely various selective beta₂-adrenergic agonist, corticosteroid, and more recently leukotriene antagonist substitution. However, these compounds also have various limitations, and therefore, it is desired to develop a theophylline-like drug with reduced side effects.

It is now recognized that caffeine, and its close analog, blocks endogenous adenosine, which acts as a local modulator of adenosine receptors in the brain and other organs, at therapeutically useful doses. Adenosine kinaseFour subtypes of G-protein coupled Adenosine Receptors (AR), A, are activated₁/A_2A/A_2B/A₃. Enprophylline (Compound B, lower panel)

Is reportedly capable of blocking A_2BAnother example of xanthine, the adenosine receptor, is used to treat asthma. However, this compound only weakly blocks A₁、A_2AAnd A₃The adenosine receptor. Selective adenosine a has also been indicated by LaNoue et al (U.S. patent No. 6,060,481)_2BAntagonists may be used to improve insulin sensitivity in a patient.

Therapeutic concentrations of theophylline or enprophylline have been reported to block A in humans_2BReceptors, and it is recommended that antagonists selective for this subtype may have potential use as anti-asthmatic agents. (see Feoktisov, I. et al, Pharmacol. Rev.1997, 49, 381-402; and Robeva, A.S. et al, Drug Dev. Res.1996, 39, 243-252). Reported K of enprophylline_iHas a value of 7 μ M and binds to human A_2BThe AR aspect has some degree of selectivity. (see Robeva, A.S. et al, Drug Dev. Res.1996, 39, 243- "252 and Linden, J. et al, mol. Pharmacol.1999, 56, 705-" 713). A. the_2BAR is expressed as BR line (BR line) in some mast cells (e.g., breast cell tumor canine cells), and can be considered to trigger acute Ca²⁺The cause of migration and degranulation. (see Auchampach, J.A. et al, mol. Pharmacol.1997, 52, 846-. A. the_2BAR also initiates Ca²⁺And involved in the delayed release of IL8 from human HMC-1 mast cells. Others with A_2BAR-associated functions also control cell growth and gene expression (see, nery, J. et al, Trends neurosci.1996, 19, 13-18), endothelium-dependent vasodilation (see, Martin, P.L. et al, J. Pharmacol. exp. Ther.1993, 265, 248-Fluid is secreted in the epithelium (see Strohmeier, G.R. et al, J.biol.chem.1995, 270, 2387-. It has also been reported that adenosine can pass through A_2BThe AR acts to promote chloride permeability in cells expressing the cystic fibrosis transport regulator (see Clancy, J.P. et al, am.J.Physiol.1999, 276, C361-C369).

Recently Linden et al (U.S. patent No. 6,545,002) described a novel group of compounds and pharmaceutical compositions, which are a_2BSelective antagonists of Adenosine Receptors (ARs).

Albeit for A₁、A_2AAnd A₃AR, adenosine receptor subtype-selective probes (probes) are available, but for A_2BFew selective antagonists and no selective agonists are known for the receptor. Thus, there is still a need to seek various alternatives A_2BA compound which is a receptor antagonist.

Summary of The Invention

The present invention provides various uses as A_2BCompounds which are adenosine receptor antagonists. Accordingly, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

wherein:

r is hydrogen or (C)₁-C₅) Alkyl, halo (C)₁-C₈) Alkyl, (C)₃-C₅) Alkenyl or (C)₃-C₅) An alkynyl group;

R¹and R²Independently hydrogen, (C)₁-C₈) Alkyl, (C)₃-C₈) Alkenyl, (C)₃-C₈) Alkynyl, (C)₁-C₈) Alkoxy group, (C)₃-C₈) Cycloalkyl group, (C)₃-C₈) Cycloalkyl (C)₁-C₈) Alkyl, (C)₄-C₁₀) Heterocyclic group, (C)₄-C₁₀) Heterocyclic radical (C)₁-C₈) Alkyl, (C)₆-C₁₀) Aryl group, (C)₆-C₁₀) Aryl radical (C)₁-C₈) Alkyl, (C)₅-C₁₀) Heteroaryl or (C)₅-C₁₀) Heteroaryl (C)₁-C₈) An alkyl group;

x is a compound having 1 nitrogen atom optionally substituted by 1, 2 or 3 nonperoxy groups (-O-), thio groups (-S-), sulfinyl groups (-SO-), sulfonyl groups (-S (O)₂-) or amine-N (R)⁹) -a interrupted 5-10 membered heteroaryl ring;

z is-OR³、-SR³Halogen, -S (O)_m-NR⁴R⁵、-NR⁴R⁵Or (C)₄-C₁₀) Heterocyclyl, wherein said heterocyclyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: halogen, cyano, nitro, -OR^a、-SR^a、(C₁-C₈) Alkyl, (C)₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c；

Each Z¹Independently is (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl, (C)₂-C₈) Alkynyl, -OR⁶、-SR⁶Halogen, R⁶O(C₁-C₈) Alkyl radical, R⁷R⁸N(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR⁷R⁸、R⁷R⁸N(C₁-C₈) Alkyl, -C (O) R⁶、-COOR⁶and-C (O) NR⁷R⁸；

R³Is (C)₁-C₈) Alkyl, (C)₃-C₈) Alkenyl, (C)₃-C₈) Alkynyl, (C)₆-C₁₀) Aryl group, (C)₆-C₁₀) Aryl radical (C)₁-C₈) Alkyl, (C)₅-C₁₀) Heteroaryl, (C)₅-C₁₀) Heteroaryl (C)₁-C₈) Alkyl, -C (O) R⁶or-C (O) NR⁷R⁸；

R⁴And R⁵Independently hydrogen, (C)₁-C₈) Alkyl, (C)₃-C₈) Alkenyl, (C)₃-C₈) Alkynyl, (C)₁-C₈) Alkoxy group, (C)₃-C₈) Cycloalkyl group, (C)₃-C₈) Cycloalkyl (C)₁-C₈) Alkyl, (C)₆-C₁₈) Polycyclic alkyl radical, (C)₆-C₁₈) Polycyclic alkyl radical (C)₁-C₈) Alkyl, (C)₃-C₁₀) Heterocyclic group, (C)₃-C₁₀) Heterocyclic radical (C)₁-C₈) Alkyl, -NR⁷R⁸、(C₆-C₁₀) Aryl group, (C)₆-C₁₀) Aryl radical (C)₁-C₈) Alkyl, (C)₅-C₁₀) Heteroaryl, (C)₅-C₁₀) Heteroaryl (C)₁-C₈) Alkyl, - (C)₂-C₄-Y)_q-(CH₂)_2-4-X¹、-C(O)R⁶、-CO₂R⁶、-C(O)NR⁷R⁸or-S (O)₂-NR⁷R⁸(ii) a Or R⁴And R⁵Together with the atoms to which they are attached form a cyclic ring having 3, 4,5, 6, 7 or 8 ring atoms and optionally containing 1, 2, 3 or 4 ring atoms selected from nonperoxyoxy (-O-), thio (-S-), sulfinyl (-SO-), sulfonyl (-S (O)₂-) and amine-N (R)⁹) -a saturated or partially unsaturated monocyclic, bicyclic or aromatic ring of a heteroatom, wherein said ring is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: halogen, cyano, nitro,-OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c；

X¹is-OR⁶、-C(O)R⁶、-CO₂R⁶or-NR⁷R⁸(ii) a And Y is oxy (-O-), thio (-S-), sulfinyl (-SO-), sulfonyl (-S (O)₂-) and amine-N (R)^b)-；

Wherein R is¹、R²、R³、R⁴And R⁵The alkyl, alkenyl, cycloalkyl, alkynyl, aryl, heterocyclyl or heteroaryl groups of the group are optionally substituted with one or more substituents independently selected from: halogen, cyano, nitro, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c；

Wherein R is⁶Is hydrogen, (C)₁-C₈) Alkyl radical, R^aO(C₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, (C)₃-C₁₀) Heterocyclic group, (C)₃-C₁₀) Heterocyclic radical (C)₁-C₈) Alkyl, (C)₆-C₁₀) Aryl group, (C)₆-C₁₀) Aryl radical (C)₁-C₈) Alkyl, (C)₄-C₁₀) Heteroaryl, (C)₄-C₁₀) Heteroaryl (C)₁-C₈) An alkyl group; wherein said heterocyclyl, heteroaryl or aryl is optionally substituted by 1, 2, 3Or 4 substituents independently selected from: halogen, cyano, nitro, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c；

Wherein R is⁷、R⁸And R⁹Independently hydrogen, (C)₁-C₈) Alkyl radical, R^aO(C₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, (C)₃-C₁₀) Heterocyclic group, (C)₆-C₁₀) Aryl group, (C)₆-C₁₀) Aryl radical (C)₁-C₈) Alkyl, (C)₄-C₁₀) Heteroaryl, -COOR^a、-C(O)R^aor-C (O) NR^bR^cWherein said heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: halogen, cyano, nitro, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c(ii) a Or R⁷And R⁸Together with the atoms to which they are attached form a saturated or partially unsaturated monocyclic, bicyclic or aromatic ring having 3, 4,5, 6, 7 or 8 ring atoms, optionally the ring has 4 to 8 ring atoms and optionally contains 1, 2, 3 or 4 atoms in the ring selected from nonperoxyoxy (-O-), thio (-S-), sulfinyl (-SO-), sulfonyl (-S (O)₂-) or amine-N (R)⁹) -a heteroatom of (a);

R^ais hydrogen or (C)₁-C₆) An alkyl group; r^bAnd R^cEach independently of the other is hydrogen or (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₃-C₈) Cycloalkyl group, (C)₁-C₆) Alkylthio group, (C)₆-C₁₀) Aryl group, (C)₆-C₁₀) Aryl radical (C)₁-C₆) Alkyl, heteroaryl or heteroaryl (C)₁-C₆) An alkyl group; or R^bAnd R^cTogether with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, azaRadical diazaA morpholinyl or thiomorpholinyl ring; and

wherein n is 0, 1, 2, 3, 4,5, 6, 7 or 8; m is 1 or 2; and q is 1, 2, 3 or 4.

The invention also provides pharmaceutically acceptable salts of the compounds of formula (I). The invention also provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

In addition, the present invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal (e.g., a human), wherein adenosine A is administered to the mammal_2BReceptor activity (i.e., overactivity) is associated with one or more symptoms of the pathology, and antagonism (i.e., blockade) of these activities is required in order to ameliorate the symptoms. Such diseases or conditions include, but are not limited to, asthma, allergy, allergic diseases (such as allergic rhinitis and sinusitis), autoimmune diseases (such as lupus), diarrheal diseases, insulin resistance, diabetes, prevention of massive cell degranulation associated with ischemia/reperfusion injury, heart attack, inhibition of angiogenesis in tumor tissue, and inhibition of angiogenesis in diabetic retinopathy or hyperbaric oxygen induced retinopathy. The invention also includes a therapeutic feedA method of inhibiting asthma, diarrheal disease, insulin resistance, diabetes, angiogenesis in tumor tissue and inhibiting angiogenesis in diabetic retinopathy or hyperbaric oxygen induced retinopathy in a dairy animal (such as a human) which comprises administering to a mammal in need of such treatment an effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof.

The present invention provides a compound of formula I for use in medical therapy, preferably for use in the treatment of a disease or disorder_2BVarious diseases or disorders associated with receptor activation or activity, including asthma, diarrheal disease, insulin resistance, diabetes, ischemia/reperfusion injury, inhibition of angiogenesis in tumor tissue, and inhibition of angiogenesis in diabetic retinopathy or hyperbaric oxygen induced retinopathy.

The invention also provides the use of a compound of formula I in the manufacture of a medicament for the treatment of a pathological condition or symptom associated with deleterious a in a mammal (e.g., a human)_2BReceptor activation or activity is relevant, including the various diseases or conditions described above.

The invention also includes a method comprising contacting a sample, optionally with a radioisotope (radionuclide) such as tritium, radioiodine (e.g., for use in binding assays)¹²⁵I or for spectral imaging¹²³I) Etc. with object A comprising said receptor_2BAdenosine receptor sites are contacted in vivo or in vitro to bind to the receptor. Comprising a binding A_2BCell membranes at adenosine receptor sites can be used to determine the selectivity of test compounds for various adenosine receptor subtypes or can be used to identify compounds for treatment and A_2BMeans for the potential treatment of a drug for a variety of diseases or conditions associated with receptor-mediated effects by contacting the drug with the radioligand and a receptor and then determining the extent of displacement of the radioligand and/or the binding of the drug.

Detailed Description

The applicant finds thatThe compounds of the invention having formula I are useful for treating and preventing A_2BVarious diseases or conditions associated with receptor activation or activity.

Unless otherwise stated, the following definitions are used: halogen is fluorine, chlorine, bromine or iodine. Alkyl, alkoxy, alkenyl, alkynyl, and the like refer to both straight and branched chain groups; however, reference to a single group such as "propyl" includes only straight chain groups and branched chain isomers such as "isopropyl" will be explicitly indicated. When the alkyl group may be partially unsaturated, the alkyl chain may contain one or more (e.g. 1, 2, 3 or 4) double or triple bonds in the chain.

"aryl" refers to a phenyl group or a single-sided fused bicyclic carbocyclic group having about 9 to 10 ring atoms in which at least one ring is aromatic.

"aralkyl" or "(C)₆-C₁₀) Aryl radical (C)₁-C₈) Alkyl "refers to the formula: aryl radical (C)₁-C₈) Radical of alkyl, where aryl and (C)₁-C₈) Alkyl is as defined herein.

"Heterocyclyl" includes saturated or unsaturated monocyclic, fused bicyclic or bridged bicyclic ring radicals which are linked via a ring nitrogen or a ring carbon atom and which are composed of carbon atoms and 1, 2, 3 or 4 heteroatoms, the ring system containing from 5 to 10 ring atoms, preferably from 5 to 6 ring atoms, each heteroatom being selected from the group consisting of: nonperoxyoxy (-O-), thio (-S-), sulfinyl (-SO-), sulfonyl (-S (O)₂-), amine-N (R)⁹) -or-N ═ group, where R is⁹As defined herein, and optionally contains 1-3 double bonds (e.g., -CH ═ CH-or-CH ═ N-). Heterocyclyl includes, for example, tetrahydrofuryl, dihydrofuryl, tetrahydroimidazolyl, azaborolinyl (norornyl), pyrrolidinyl, piperidinyl, piperazinyl (piperizyl), morpholinyl, azanyl1, 3-diazepine, and their use as basesRadical, 1, 3-benzodiazepines1, 4-diazepinesRadical, 1, 4-benzodiazepines1, 5-diazepinesRadical, 1, 5-benzodiazepinesAnd the like.

"heteroaryl" includes the group of monocyclic aromatic rings linked by ring atoms consisting of carbon atoms and 1, 2, 3 or 4 heteroatoms, containing from 5 to 10 ring atoms, preferably from 5 to 6 ring atoms, each heteroatom being selected from the following groups: nonperoxyoxy (-O-), thio (-S-), sulfinyl (-SO-), sulfonyl (-S (O)₂-) or an amine group (-N (R)⁹) -⁹As defined herein. Preferred heteroaryl groups include imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, pyrimidinyl, indolyl, isoquinolyl, quinolinyl and the like.

As recognized by those skilled in the art, the imidazole ring of the compounds of the present invention may exist in tautomeric forms or as tautomers and are therefore also encompassed within the scope of the present invention. Tautomers are represented by the following structures (Ia) and (Ib):

for example, for the purposes of this application, the tautomers (Ia) and (Ib) are also meant when a compound (I) is named or referred to. Similarly, for the purposes of this application, when referring to the compound (Ia) the tautomers (I) and (Ib) are also meant. The same is true for tautomer (Ib).

"optional" or "optionally" means that the subsequently described event or condition may, but need not, occur, and that the description includes both the occurrence of the event or condition and the absence of the event or condition. For example, "optionally substituted" means that the indicated substituent may be present, but need not be present, and that the description includes instances where the indicated substituent is included and instances where the indicated substituent is not included.

The terms "comprising," "for example," "such as," and the like are used for illustrative purposes and are not intended to limit the present invention.

Reference herein to substances is to such substances unless otherwise indicated.

It will be appreciated by those skilled in the art that compounds of the invention having chiral centers may exist and be resolved in both optically and racemic forms. Some compounds may exhibit polymorphism. It is understood that the invention also includes any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention which possesses the useful properties described herein, and it is well known in the art how to prepare optically active forms (e.g., by resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to assay, for example, anticancer, herbicidal, or other therapeutic activity using the standard assays described herein or using other similar assays well known in the art.

The specific values and preferred values for the various groups, substituents and ranges set forth below are for purposes of example only; for each group and substituent, they do not exclude other defined values or other values within the defined ranges.

Specifically, (C)₁-C₈) The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 3-pentyl, n-hexyl, n-heptyl, n-octyl, or branched (C)₃-C₈) An alkyl group; (C)₂-C₈) The alkenyl group may be vinyl, 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, or branched (C)₃-C₈) An alkenyl group; (C)₃-C₈) The alkenyl group may be 2-propenyl (allyl), 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 2-octenyl, 3-octenyl, 4-octenyl, or branched (C)₃-C₈) An alkyl group; (C)₂-C₈) The alkynyl group may be ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 1-octynyl, 2-octynyl, 3-octynyl, 4-octynyl, or branched (C₃-C₈) An alkynyl group; (C)₃-C₈) The alkynyl group may be 2-propynyl (propargyl), 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 1-octynyl, 2-octynyl, 3-octynyl, 4-octynyl or branched (C)₃-C₈) An alkynyl group; (C)₁-C₈) The alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, 3-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy, or branched (C)₃-C₈) An alkoxy group; halo (C)₁-C₈) The alkyl group can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl2-bromoethyl, 2-fluoroethyl, 3-fluoropropyl, 2, 2, 2-trifluoroethyl, pentafluoroethyl, or branched halo (C)₃-C₈) An alkyl group; (C)₃-C₈) Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; (C)₃-C₈) Cycloalkyl (C)₁-C₈) The alkyl group may be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl or 2-cyclohexylethyl; (C)₆-C₁₀) Aryl may be phenyl, indenyl or naphthyl; the heterocyclic group may be tetrahydrofuryl, dihydrofuryl, tetrahydroimidazolyl, azaborolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, aza-1, 3-diazepine, and their use as basesRadical, 1, 3-benzodiazepines1, 4-diazepinesRadical, 1, 4-benzodiazepines1, 5-diazepinesRadical or 1, 5-benzodiazepinesAnd (4) a base.

Aralkyl may be phenylethyl, benzyl, 2-phenylpropyl, 3-phenylpropyl, 2-naphthylmethyl or 3-naphthylmethyl; heteroaryl groups can be imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, pyrimidinyl, indolyl, isoquinolyl, quinolinyl, or oxides thereof.

(C₁-C₈) The alkyl group may be methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl; the alkenyl group may be ethenyl, propenyl, butenyl, pentenyl and hexenyl.

Specific cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Specific cycloalkylalkyl groups are cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylethyl and 2-cyclohexylethyl.

Specific aryl groups are phenyl, indenyl or naphthyl.

Specific aralkyl groups are benzyl and 2-phenylethyl.

Specific haloalkyl groups are bromoethyl, chloroethyl, fluoroethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl or 3-fluoropropyl.

A particular group of values for R is hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, n-butyl, isobutyl or halo (C)₁-C₄) An alkyl group.

Another group of specific values of R is hydrogen, methyl, ethyl, -CH₂-CH₂-Cl、-CH₂-CH₂-Br or-CH₂-CH₂-CH₂-F。

Another set of specific values for R is hydrogen.

R¹A specific group of values of (A) is hydrogen, (C)₁-C₄) Alkyl, (C)₃-C₄) Alkenyl, (C)₃-C₄) Alkynyl, phenyl or phenyl (C)₁-C₄) An alkyl group.

R¹Another set of specific values of (C)₃-C₆) Cycloalkyl and (C)₃-C₆) Cycloalkyl (C)₁-C₄) An alkyl group.

R¹Is cyclopropyl or cyclopropylmethyl.

R¹Is hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, n-butyl, isobutyl, phenyl, phenethyl or benzyl.

R¹Another group of specific values of (a) is hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl or (methoxyphenyl) ethyl.

R¹Another group of specific values of (a) is ethyl, n-propyl or allyl.

R²A specific group of values of (A) is hydrogen, (C)₁-C₄) Alkyl, (C)₃-C₄) Alkenyl, (C)₃-C₄) Alkynyl, phenyl or phenyl (C)₁-C₄) An alkyl group.

R²Another set of specific values of (C)₃-C₆) Cycloalkyl and (C)₃-C₆) Cycloalkyl (C)₁-C₄) An alkyl group.

R²Is cyclopropyl or cyclopropylmethyl.

R²Another group of specific values of hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, n-butyl, isobutyl, phenyl, phenethyl or benzyl.

R²Another group of specific values of (a) is hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl or (methoxyphenyl) ethyl.

R²Another group of specific values of (a) is ethyl, n-propyl or allyl.

One specific group of X is imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl,Thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, pyrimidinyl, indolyl, isoquinolyl or quinolinyl, each optionally substituted with 1, 2 or 3 substituents independently selected from: halogen, cyano, nitro, (C)₁-C₈) Alkyl, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c。

Another group of specific values for X is 2-pyridyl, 3-pyridyl, or 4-pyridyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: halogen, cyano, nitro, (C)₁-C₈) Alkyl, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c。

-X(Z¹)_nA particular group of values of Z is a group having the formula:

-X(Z¹)_nanother specific set of values for-Z is a group having the formula:

a specific group of values for Z is-OH, -O (C)₁-C₄) Alkyl, -O (C)₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl radical (C)₁-C₄) Alkyl, -NR⁴R⁵F, Cl, Br or I.

Another group of specific values of Z is-NR⁴R⁵。

Another set of specific values for Z is:

R⁴a specific group of values of (A) is hydrogen, (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl (C)₁-C₄) Alkyl, (C)₃-C₆) Heterocyclic group, (C)₆-C₁₀) Aryl group, (C)₆-C₁₀) Aryl radical (C)₁-C₄) Alkyl, (C)₅-C₆) Heteroaryl radicalOr (C)₅-C₆) Heteroaryl (C)₁-C₄) Alkyl, -S (O)₂)NH₂、-C(O)R⁶、-CO₂R⁶or-C (O) NR⁶R⁷。

R⁴Another group of specific values of (A) is hydrogen, (C)₁-C₄) Alkyl, hydroxy (C)₂-C₄) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₆-C₁₀) Aryl group, (C)₇-C₁₀) Aralkyl, (C)₅-C₆) Heteroaryl, - (CH)₂-CH₂-O)_q-(CH₂-CH₂)-OR^a、-(CH₂-CH₂-O)_q-(CH₂-CH₂)-COOR^a、-(CH₂-CH₂-O)_q-(CH₂-CH₂)-NR^aR^b、-NR⁷R⁸、-C(O)R⁶、-CO₂R⁶or-C (O) NR⁷R⁸。

R⁴Another group of specific values of (A) is hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethyl, methylbenzyl, aminomethylbenzyl, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, thienyl, -C (O) R⁶、-CO₂R⁶or-C (O) NHR⁷。

R⁴Another group of values of (A) is methyl, ethyl, cyclopropyl, cyclopropylmethyl, -C (O) R⁶、-CO₂R⁶or-C (O) NHR⁷。

R⁵A specific group of values of (A) is hydrogen, (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl (C)₁-C₄) Alkyl, (C)₃-C₆) Heterocyclic group, (C)₆-C₁₀) Aryl group, (C)₆-C₁₀) Aryl radical (C)₁-C₄) Alkyl, (C)₅-C₆) Heteroaryl or (C)₅-C₆) Heteroaryl (C)₁-C₄) Alkyl, -S (O)₂)NH₂、-C(O)R⁶、-CO₂R⁶or-C (O) NR⁶R⁷。

R⁵Another group of specific values of (A) is hydrogen, (C)₁-C₄) Alkyl, hydroxy (C)₂-C₄) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₆-C₁₀) Aryl group, (C)₇-C₁₀) Aralkyl, (C)₅-C₆) Heteroaryl, - (CH)₂-CH₂-O)_q-(CH₂-CH₂)-OR^a、-(CH₂-CH₂-O)_q-(CH₂-CH₂)-COOR^a、-(CH₂-CH₂-O)_q-(CH₂-CH₂)-NR^aR^b、-NR⁷R⁸、-C(O)R^b、-CO₂R⁶or-C (O) NR⁷R⁸。

R⁵Another group of specific values of (A) is hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethyl, methylbenzyl, aminomethylbenzyl, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, thienyl, -C (O) R⁶、-CO₂R⁶or-C (O) NHR⁷。

R⁵Another group of values of (A) is methyl, ethyl, cyclopropyl, cyclopropylmethyl, -C (O) R⁶、-CO₂R⁶or-C (O) NHR⁷。

R⁴And R⁵The radicals formed together with the nitrogen to which they are attached have the specific meaning pyrrolidinyl, piperidinyl, piperazinyl, azaRadical diazaA morpholinyl or thiomorpholinyl ring, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from: halogen, cyano, nitro, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c。

R⁶A specific set of values of (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl (C)₁-C₄) Alkyl, (C)₃-C₆) Heterocyclic group, (C)₆-C₁₀) Aryl group, (C)₆-C₁₀) Aryl radical (C)₁-C₄) Alkyl, (C)₅-C₆) Heteroaryl or (C)₅-C₆) Heteroaryl (C)₁-C₄) Alkyl, each optionally substituted with 1, 2 or 3 substituents independently selected from: halogen, cyano, nitro, (C)₁-C₈) Alkyl, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c。

R⁶Another set of specific values of (C)₆-C₁₀) Aryl group, (C)₅-C₆) Heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from: halogen, cyano, nitro, (C)₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -COOR^aand-C (O) NR^bR^c。

R⁶Is pyridyl, optionally substituted by F, Cl, Br, I, CF₃Cyano, nitro, -COOR^aor-CONHR^aAnd (4) substitution.

Another particular class of such compounds are those wherein R is hydrogen, methyl or ethyl; r¹And R²Independently methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl; x is a 3-pyridyl group substituted at the 6-position by Z, wherein Z is (C)₄-C₁₀) Heterocyclyl or-NR⁴R⁵；R⁴Is methyl, ethyl, cyclopropyl, cyclopropylmethyl and R⁵is-C (O) R⁶Wherein R is⁶Is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, cyano, nitro, halo (C)₁-C₈) Alkyl, -C (O) R^a、-COOR^aand-C (O) NR^bR^cSubstituted heteroaryl, wherein R^a、R^bAnd R^cIndependently hydrogen, methyl, ethyl, propyl, isopropyl or cyclopropyl.

The compounds of the present invention may have the formula:

aspects of the invention

The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

wherein:

Each Z¹Independently is (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl, (C)₂-C₈) Alkynyl, -OR⁶、-SR⁶Halogen, R⁶O(C₁-C₈) Alkyl radical、R⁷R⁸N(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR⁷R⁸、R⁷R⁸N(C₁-C₈) Alkyl, -C (O) R⁶、-COOR⁶and-C (O) NR⁷R⁸；

R⁴And R⁵Independently hydrogen, (C)₁-C₈) Alkyl, (C)₃-C₈) Alkenyl, (C)₃-C₈) Alkynyl, (C)₁-C₈) Alkoxy group, (C)₃-C₈) Cycloalkyl group, (C)₃-C₈) Cycloalkyl (C)₁-C₈) Alkyl, (C)₆-C₁₈) Polycyclic alkyl radical, (C)₆-C₁₈) Polycyclic alkyl radical (C)₁-C₈) Alkyl, (C)₃-C₁₀) Heterocyclic group, (C)₃-C₁₀) Heterocyclic radical (C)₁-C₈) Alkyl, -NR⁷R⁸、(C₆-C₁₀) Aryl group, (C)₆-C₁₀) Aryl radical (C)₁-C₈) Alkyl, (C)₅-C₁₀) Heteroaryl, (C)₅-C₁₀) Heteroaryl (C)₁-C₈) Alkyl, - (C)₂-C₄-Y)_q-(CH₂)_2-4-X¹、-C(O)R⁶、-CO₂R⁶、-C(O)NR⁷R⁸or-S (O)₂-NR⁷R⁸(ii) a Or R⁴And R⁵Together with the atoms to which they are attached form a ring having 3, 4,5, 6, 7 or 8 ring atoms and optionally containing 1, 2, 3 or 4 atoms in the ring selected from non-peroxyOxy (-O-), thio (-S-), sulfinyl (-SO-), sulfonyl (-S (O)₂-) and amine-N (R)⁹) -a saturated or partially unsaturated monocyclic, bicyclic or aromatic ring of a heteroatom, wherein said ring is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: halogen, cyano, nitro, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c；

X¹is-OR⁶、-C(O)R⁶、-CO₂R⁶or-NR⁷R⁸(ii) a And Y is oxy (-O-), thio (-S-), sulfinyl (-SO-), sulfonyl (-S (O)₂-) and amine-N (R)⁹)-；

Wherein R is⁶Is hydrogen, (C)₁-C₈) Alkyl radical, R^aO(C₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, (C)₃-C₁₀) Heterocyclic group, (C)₃-C₁₀) Heterocyclic radical (C)₁-C₈) Alkyl, (C)₆-C₁₀) Aryl group, (C)₆-C₁₀) Aryl radical (C)₁-C₈) Alkyl, (C)₄-C₁ ⁰) Heteroaryl, (C)₄-C₁₀) Heteroaryl (C)₁-C₈) An alkyl group; wherein said heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: halogen, cyano, nitro, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c；

Wherein R is⁷、R⁸And R⁹Independently hydrogen, (C)₁-C₈) Alkyl radical, R^aO(C₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, (C)₃-C₁₀) Heterocyclic group, (C)₆-C₁₀) Aryl group, (C)₆-C₁₀) Aryl radical (C)₁-C₈) Alkyl, (C)₄-C₁₀) Heteroaryl, -COOR^a、-C(O)R^aor-C (O) NR^bR^cWherein said heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: halogen, cyano, nitro, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c(ii) a Or R⁷And R⁸Together with the atoms to which they are attached form a saturated or partially unsaturated monocyclic, bicyclic or aromatic ring having 3, 4,5, 6, 7 or 8 ring atoms, optionally the ringHaving 4 to 8 ring atoms and optionally containing 1, 2, 3 or 4 atoms in the ring selected from nonperoxy (-O-), thio (-S-), sulfinyl (-SO-), sulfonyl (-S (O))₂-) or amine-N (R)^b) -a heteroatom of (a);

wherein n is 0, 1, 2, 3, 4,5, 6, 7 or 8; m is 1 or 2; and q is 1, 2, 3 or 4.

In one aspect of the invention, R is hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, n-butyl, isobutyl, or halo (C)₁-C₄) An alkyl group. In another aspect of the invention, R is hydrogen, methyl, ethyl, -CH₂-CH₂-Cl、-CH₂-CH₂-Br or-CH₂-CH₂-CH₂-F. In one variation, R is hydrogen.

In one aspect of the present invention, there is provided the above compound wherein R is¹Is hydrogen, (C)₁-C₄) Alkyl, (C)₃-C₄) Alkenyl, (C)₃-C₄) Alkynyl, phenyl or phenyl (C)₁-C₄) An alkyl group. In another aspect of the inventionIn aspect, R¹Is (C)₃-C₆) Cycloalkyl and (C)₃-C₆) Cycloalkyl (C)₁-C₄) An alkyl group. In one variant, R¹Is cyclopropyl or cyclopropylmethyl. In another variant, R¹Hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, n-butyl, isobutyl, phenyl, phenethyl, benzyl or (methoxyphenyl) ethyl. In yet another variation, R¹Is ethyl, n-propyl or allyl.

In one aspect of the present invention, there is provided the above compound wherein R is²Is hydrogen, (C)₁-C₄) Alkyl, (C)₃-C₄) Alkenyl, (C)₃-C₄) Alkynyl, phenyl (C)₁-C₄) Alkyl or (methoxyphenyl) ethyl. In one variant, R²Is (C)₃-C₆) Cycloalkyl or (C)₃-C₆) Cycloalkyl (C)₁-C₄) An alkyl group. In another variant, R²Is cyclopropyl or cyclopropylmethyl. In yet another variation, R²Hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, n-butyl, isobutyl, phenyl, phenethyl or benzyl. In yet another variation, R²Is ethyl, n-propyl or allyl.

In one aspect of the present invention, there are provided the above compounds wherein Z is-OH, -O (C)₁-C₄) Alkyl, -O (C)₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl radical (C)₁-C₄) Alkyl, -NR⁴R⁵F, Cl, Br or I.

In another aspect of the present invention, there is provided the above compound wherein R is⁴Is hydrogen, (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl (C)₁-C₄) Alkyl, (C)₃-C₆) Heterocyclic group, (C)₆-C₁₀) Aryl group, (C)₆-C₁₀) Aryl radical (C)₁-C₄) Alkyl, (C)₅-C₆) Heteroaryl or (C)₅-C₆) Heteroaryl (C)₁-C₄) Alkyl, -S (O)₂)NH₂、-C(O)R⁶、-CO₂R⁶or-C (O) NR⁶R⁷. In one variant, R⁴Is hydrogen, (C)₁-C₄) Alkyl, hydroxy (C)₂-C₄) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₆-C₁₀) Aryl group, (C)₇-C₁₀) Aralkyl, (C)₅-C₆) Heteroaryl, - (CH)₂-CH₂-O)_q-(CH₂-CH₂)-OR^a、-(CH₂-CH₂-O)_q-(CH₂-CH₂)-COOR^a、-(CH₂-CH₂-O)_q-(CH₂-CH₂)-NR^aR^b、-NR⁷R⁸、-C(O)R⁶、-CO₂R⁶or-C (O) NR⁷R⁸. In yet another variation, R⁴Is hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethyl, methylbenzyl, aminomethylbenzyl, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, thienyl, -C (O) R⁶、-CO₂R⁶or-C (O) NHR⁷. In yet another variation, R⁴Is methyl, ethyl, cyclopropyl, cyclopropylmethyl, -C (O) R⁶、-CO₂R⁶or-C (O) NHR⁷。

In one aspect of the present invention, there is provided the above compound wherein R is⁵Is hydrogen, (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl (C)₁-C₄) Alkyl, (C)₃-C₆) Heterocyclic group, (C)₆-C₁₀) Aryl group, (C)₆-C₁₀) Aryl radical (C)₁-C₄) Alkyl, (C)₅-C₆) Heteroaryl, (C)₅-C₆) Heteroaryl (C)₁-C₄) Alkyl, -S (O)₂)NH₂、-C(O)R⁶、-CO₂R⁶or-C (O) NR⁶R⁷. In one variant, R⁵Is hydrogen, (C)₁-C₄) Alkyl, hydroxy (C)₂-C₄) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₆-C₁₀) Aryl group, (C)₇-C₁₀) Aralkyl, (C)₅-C₆) Heteroaryl, - (CH)₂-CH₂-O)_q-(CH₂-CH₂)-OR^a、-(CH₂-CH₂-O)_q-(CH₂-CH₂)-COOR^a、-(CH₂-CH₂-O)_q-(CH₂-CH₂)-NR^aR^b、-NR⁷R⁸、-C(O)R⁶、-CO₂R⁶or-C (O) NR⁷R⁸. In another variant, R⁵Is hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethyl, methylbenzyl, aminomethylbenzyl, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, thienyl, -C (O) R⁶、-CO₂R⁶or-C (O) NHR⁷. In yet another variation, R⁵Is methyl, ethyl, cyclopropyl, cyclopropylmethyl, -C (O) R⁶、-CO₂R⁶or-C (O) NHR⁷。

In one aspect of the present invention, there is provided the above compound wherein R is⁴And R⁵Together with the nitrogen to which they are attached is pyrrolidinyl, piperidinyl, piperazinyl, azaRadical diazaA morpholinyl or thiomorpholinyl ring, each optionally substituted by 1, 2, 3 or 4 independently selected fromThe substituent (b): halogen, cyano, nitro, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c。

In another aspect of the present invention, there is provided the above compound wherein R is⁶Is (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl (C)₁-C₄) Alkyl, (C)₃-C₆) Heterocyclic group, (C)₆-C₁₀) Aryl group, (C)₆-C₁₀) Aryl radical (C)₁-C₄) Alkyl, (C)₅-C₆) Heteroaryl or (C)₅-C₆) Heteroaryl (C)₁-C₄) Alkyl, each optionally substituted with 1, 2 or 3 substituents independently selected from: halogen, cyano, nitro, (C)₁-C₈) Alkyl, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c. In one variant, R⁶Is (C)₆-C₁₀) Aryl group, (C)₅-C₆) Heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from: halogen, cyano, nitro, (C)₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -COOR^aand-C (O) NR^bR^c. In another variant, R⁶Is pyridyl, optionally substituted by F, Cl, Br, I, CF₃Cyano, nitro, -COOR^aor-CONHR^aAnd (4) substitution.

Another particular such compound is one wherein R is hydrogen, methyl or ethyl; r¹And R²Independently is methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl or n-butyl; x is a 3-pyridyl group substituted at the 6-position by Z, wherein Z is (C)₄-C₁₀) Heterocyclyl or-NR⁴R⁵；R⁴Is methyl, ethyl, cyclopropyl, cyclopropylmethyl and R⁵is-C (O) R⁶Wherein R is⁶Is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, cyano, nitro, halo (C)₁-C₈) Alkyl, -C (O) R^a、-COOR^aand-C (O) NR^bR^cSubstituted heteroaryl, wherein R^a、R^bAnd R^cIndependently hydrogen, methyl, ethyl, propyl, isopropyl or cyclopropyl.

In another aspect of the present invention, there are provided the above compounds wherein R is hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, n-butyl, isobutyl or halo (C)₁-C₄) An alkyl group; and R¹And R²Independently hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl, isobutyl, phenyl, phenethyl or benzyl. In one variant, R is hydrogen, methyl, ethyl, -CH₂-CH₂-Cl、-CH₂-CH₂-Br or-CH₂-CH₂-CH₂-F；R¹And R²Independently hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl or (methoxyphenyl) ethyl.

In one aspect of the present invention there is provided a compound as described above wherein X is imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, pyrimidinyl, indolyl, isoquinolyl or quinolinyl, each optionally substituted with 1, 2 or 3 substituents independently selected fromSubstituent group substitution: halogen, cyano, nitro, (C)₁-C₈) Alkyl, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c. In one variation of the above, X is 2-pyridyl, 3-pyridyl, or 4-pyridyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: halogen, cyano, nitro, (C)₁-C₈) Alkyl, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c。

In another variant, -X (Z)¹)_n-Z has the formula:

in yet another variant, -X (Z)¹)_n-Z has the formula:

in one aspect of the present invention, there are provided the above compounds wherein Z is-OH, -O (C)₁-C₄) Alkyl, -OC (O) NR⁷R⁸、(C₁-C₄) Alkyl, -NR⁴R⁵F, Cl, Br or I,wherein R is⁴And R⁵Independently hydrogen, (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Heterocyclic group, (C)₆-C₁₀) Aryl group, (C)₇-C₁₂) Aralkyl, (C)₅-C₆) Heteroaryl, (C)₅-C₆) Heteroaryl (C)₁-C₄) Alkyl, -S (O)₂)NH₂、-C(O)R⁶、-CO₂R⁶or-C (O) NR⁶R⁷. In one variant, Z is-NR⁴R⁵。

In one aspect of the present invention, there is provided the above compound wherein R is⁴And R⁵Together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, azaRadical diazaA morpholinyl or thiomorpholinyl ring, wherein said ring is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: halogen, cyano, nitro, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c. In one variation of the above, R⁴And R⁵Independently hydrogen, (C)₁-C₄) Alkyl, hydroxy (C)₂-C₄) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₆-C₁₀) Aryl group, (C)₇-C₁₀) Aralkyl, (C)₅-C₆) Heteroaryl, - (CH)₂-CH₂-O)_q-(CH₂-CH₂)-OR^a、-(CH₂-CH₂-O)_q-(CH₂-CH₂)-COOR^a、-(CH₂-CH₂-O)_q-(CH₂-CH₂)-NR^aR^b、-NR⁷R⁸、-C(O)R⁶、-CO₂R⁶or-C (O) NR⁷R⁸. In another variant, R⁴And R⁵Independently hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethyl, methylbenzyl, aminomethylbenzyl, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopentyl, cyclohexyl, thienyl, -C (O) R⁶、-CO₂R⁶or-C (O) NHR⁷. In yet another variation, R⁶Is methyl, methoxy or pyridyl, R⁷Is phenyl, fluorophenyl or methoxyphenyl.

In one aspect of the present invention, there is provided the above compound, wherein R is hydrogen, methyl or ethyl; r¹And R²Independently methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl, isobutyl; and Z is (C)₄-C₁₀) Heterocyclyl, wherein said heterocyclyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: halogen, cyano, nitro, -OR^a、-SR^a、(C₆-C₁₀) Aryl, -O (C)₆-C₁₀) Aryl, hydroxy (C)₁-C₈) Alkyl radical, R^bR^cN(C₁-C₈) Alkyl, halo (C)₁-C₈) Alkyl, -NR^bR^c、-C(O)R^a、-COOR^aand-C (O) NR^bR^c。

In one aspect of the present invention, there is provided the above compound, wherein Z is selected from the group consisting of:

in one variant of the above, -X (Z)¹)_n-Z is selected from the following groups:

in another variant, R¹And R²Is n-propyl; r is hydrogen and n is 0.

In one aspect of the present invention, there is provided the above compound, wherein-X (Z)¹)_n-Z is selected from the following groups:

in one aspect of the present invention, there is provided a compound selected from the following, or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or a mixture of stereoisomers thereof:

1)	1, 3-dipropyl-8- (6-chloro-3-pyridyl) xanthine;
		2)	1-propyl-3-propargyl-8- (6-chloro-3-pyridyl) xanthine;
3)	1, 3-dipropyl-8- (6-ethylamino-3-pyridinyl) xanthine;
		4)	1, 3-dipropyl-8- [6- (2-hydroxyethyl) amino-3-pyridinyl]Xanthine;

	(vi) a purine;
		30)	1, 3-dipropyl-8- [6- (3-pentylamino) -3-pyridinyl]Xanthine;
31)	1, 3-dipropyl-8- [6- (2, 2-diphenylethylamino) -3-pyridyl]Xanthine;
		32)	1, 3-dipropyl-8- {6- [2- (1-ethylpyrrolidin-1-ylmethyl-amino)]-3-pyridyl } xanthine;
33)	1, 3-dipropyl-8- [6- (3-methoxybenzylamino) -3-pyridyl]Xanthine;
		34)	1, 3-dipropyl-8-{6- [ (N-phenylcarbamoyl) methylamino]-3-pyridyl } xanthine;
35)	1, 3-dipropyl-8- [6- (furfurylamino) -3-pyridinyl]Xanthine;
		36)	1, 3-dipropyl-8- {6- [2- (4-methoxyphenyl) ethylamino]-3-pyridyl } xanthine;
37)	1, 3-dipropyl-8- [6- (2-methoxybenzylamino) -3-pyridyl]Xanthine;
		38)	1, 3-dipropyl-8- [6- (propylamino) -3-pyridyl group]Xanthine;
39)	1, 3-dipropyl-8- [6- (cyclopentylamino) -3-pyridinyl]Xanthine;
		40)	1, 3-dipropyl-8- [6- (cyclohexylamino) -3-pyridyl]Xanthine;
41)	1, 3-dipropyl-7-ethyl-8- (6-chloro-3-pyridyl) xanthine;
		42)	1, 3-dipropyl-7- (3-fluoropropyl) -8- (6-chloro-3-pyridyl) xanthine;
43)	1, 3-dipropyl-7-methyl-8- (6-chloro-3-pyridyl) xanthine;
		44)	1, 3-dipropyl-7- (2-bromoethyl) -8- (6-chloro-3-pyridinyl) xanthine;
45)	1, 3-dipropyl-8- [6- (2-thienylmethylamino) -3-pyridinyl]Xanthine;
		46)	1, 3-dipropyl-8- {6- [ N- (4-methoxyphenyl carbamoyl) methylamino]-3-pyridyl } xanthine;
47)	1, 3-dipropyl-8- [6- (N-nicotinoylmethylamino) -3-pyridinyl]Xanthine;
		48)	1, 3-dipropyl-8- {6- [ N- (4-fluorophenylcarbamoyl) methylamino]-3-pyridyl) xanthine;
49)	1, 3-dipropyl-8- [6- (N-isonicotinyl methylamino) -3-pyridyl]Xanthine;
		50)	1, 3-dipropyl-8- [6- (N-methoxycarbonylmethylamino) -3-pyridinyl]Xanthine;
51)	1, 3-dipropyl-8- {6- [ N-phenylcarbamoyl-N- (2-phenylcarbamoyloxy)

75)	1, 3-diethyl-8- [6- (3-methoxybenzylamino) -3-pyridinyl]Xanthine;
		76)	1, 3-dipropyl-8- {6- [2- (3-pyridyl) -ethylamino]-3-pyridyl } xanthine;
77)	1, 3-diethyl-8- {6- [2- (3-pyridinyl) -ethylamino]-3-pyridyl } xanthine;
		78)	1, 3-dipropyl-8- {6- [2- (2-pyridyl) -ethylamino]-3-pyridyl } xanthine;
79)	1, 3-diethyl-8- {6- [2- (2-pyridyl) -ethylamino]-3-pyridyl } xanthine;
		80)	1, 3-diethyl-8- (6-pyrrolidinylpyridin-3-yl) xanthine;
81)	1, 3-diethyl-8- {6- [2- (1-pyrrolidinyl) -ethylamino]-3-pyridyl } xanthine;
		82)	1, 3-dipropyl-8- [6- (2-methoxyethyl) amino-3-pyridinyl]Xanthine;
83)	1, 3-dipropyl-8- [6- (2-acetylaminoethyl) amino-3-pyridyl]Xanthine;
		84)	1, 3-diethyl-8- (6-bromo-3-pyridyl) xanthine;
85)	1, 3-dipropyl-8- {6- [4- (2-pyridinyl) -piperazin-1-yl]-3-pyridyl } xanthine;
		86)	1, 3-diethyl-8- {6- [4- (2-pyridinyl) -piperazin-1-yl]-3-pyridyl } xanthine;
87)	1, 3-diethyl-8- [6- (trans-2, 5-dimethylpiperazin-1-yl) -3-pyridinyl]Xanthine;
		88)	1, 3-dipropyl-8- {6- [4- (2-pyrimidinyl) -piperazin-1-yl]-3-pyridyl } xanthine;
89)	1, 3-diethyl-8- {6- [4- (2-pyrimidinyl) -piperazin-1-yl]-3-pyridyl } xanthine;
		90)	1, 3-diethyl-8- [6- (2-methoxyethyl) amino-3-pyridinyl]Xanthine;
91)	1-propargyl-3-methyl-8- (6-bromo-3-pyridyl) xanthine;
		92)	1, 3-diethyl-8- {6- [ N-nicotinoyl-N- (2-methoxyethyl) amino]-3-pyridyl } xanthine;
93)	1-propargyl-3-methyl-8- [6- (2-methoxyethyl) -3-pyridinyl]Xanthine;
		94)	1, 3-diethyl-8- {6- [ N-isonicotinoyl-N- (2-methoxyethyl) amino]-3-pyridyl } xanthine;
95)	1- [5- (1, 3-diethyl-2, 3, 6, 7-tetrahydro-2, 6-dioxo-1H-purin-8-yl) pyridin-2-yl]-1- (2-methoxyethyl) -3- (pyridin-4-yl) urea;
		96)	1, 3-dimethyl-8- (6-bromo-3-pyridyl) xanthine;
97)	1, 3-dimethyl-8- (6-methylamino-3-pyridinyl) xanthine;
		98)	1, 3-dimethyl-8- [6- (N-nicotinoylmethylamino) -3-pyridinyl]Xanthine;

99)	1, 3-dipropyl-8- {6- [ N-nicotinoyl-N- (2-methoxyethyl) amino]-3-pyridyl } xanthine;
		100)	1-propargyl-3-methyl-8- {6- [ N-nicotinoyl-N- (2-methoxyethyl) amino]-3-pyridyl } xanthine;
101)	1-propargyl-3-methyl-8- [6- (N-nicotinoylmethylamino) -3-pyridinyl]Xanthine;
		102)	1, 3-dipropyl-8- (2, 6-dichloro-3-pyridinyl) xanthine;
103)	1, 3-dipropyl-8- (2, 6-dimethylamino-3-pyridyl) xanthine;
		104)	1, 3-dipropyl-8- [2, 6-bis (2-methoxyethyl) -3-pyridinyl]Xanthine;
105)	1, 3-dipropyl-8- [2, 6-bis (N-nicotinoylmethylamino) -3-pyridinyl]Xanthine;
		106)	1, 3-dipropyl-8- [2, 6-bis (N-nicotinoyl-N-methoxyethyl) -3-pyridinyl]Xanthine;
107)	1, 3-diethyl-8- {6- [ N- (2-pyrazinecarbonyl) methylamino]-3-pyridyl } xanthine;
		108)	1, 3-diethyl-8- {6- [ N- (isoxazole-5-carbonyl) methylamino]-3-pyridyl } xanthine;
109)	1, 3-dipropyl-8- {6- [ N- (2-pyrazinecarbonyl) methylamino]-3-pyridyl } xanthine;
		110)	1, 3-dipropyl-8- {6- [ N- (isoxazole-5-carbonyl) methylamino]-3-pyridyl } xanthine;
111)	1, 3-dipropyl-8- {6- [ N- (5-methylisoxazol-3-yl-3-carbonyl) methylamino]-3-pyridyl } xanthine;
		112)	1, 3-dipropyl-8- {6- [ N- (2-chloro-6-methoxypyridinyl-4-carbonyl) -N-methylamino]-3-pyridyl } xanthine;
113)	1, 3-dipropyl-8- {6- [ N- (isonicotinoyl N-oxide) -N-methylamino]-3-pyridyl } xanthine;
		114)	1-propyl-3- (4-methoxyphenyl) ethyl-8- (6-methylamino-3-pyridinyl) xanthine;
115)	1, 3-diethyl-8- {6- [ N- (isonicotinoyl N-oxide) -N-methylamino]-3-pyridyl } xanthine;
		116)	1, 3-diallyl-8- (6-chloro-3-pyridyl) xanthine;
117)	1-propyl-3- (4-methoxyphenyl) ethyl-8- [6- (N-nicotinoylmethylamino) -3-pyridine

	Base of]Xanthine;
		118)	1-propyl-3- (4-methoxyphenyl) ethyl-8- {6- [ N- (6-chloronicotinyl) methylamino]-3-pyridyl } xanthine;
119)	1, 3-diallyl-8- [6- (N-nicotinoylmethylamino) -3-pyridinyl]Xanthine;
		120)	1, 3-diallyl-8- {6- [ N- (6-chloronicotinyl) methylamino]-3-pyridyl } xanthine;
121)	1, 3-dipropyl-8- [6- (N- [6- (trifluoromethyl) nicotinoyl)]Methylamino) -3-pyridinyl]Xanthine;
		122)	1, 3-diethyl-8- [6- (2-hydroxy-5-methyl) benzylidenehydrazino (dehdehydro) group]-3-pyridyl]Xanthine;
123)	1-cyclopropyl-3-propyl-8- {6- [ N- (6-trifluoromethyl nicotinoyl) methylamino]-3-pyridinyl } xanthines
		124)	1, 3-diethyl-8- [6- (bromopyridine-3-methylenehydrazino) -3-pyridyl group]Xanthine;
125)	1-cyclopropyl-3-ethyl-8- (6-methylamino-3-pyridinyl) xanthine;
		126)	1-cyclopropyl-3-propyl-8- (6-methylamino-3-pyridinyl) xanthine;
127)	1-propyl-3-cyclopropyl-8- (6-methylamino-3-pyridinyl) xanthine;
		128)	1-cyclopropyl-3-propyl-8- [6- (2-methoxyethyl) amino-3-pyridinyl]Xanthine;
129)	1-cyclopropyl-3-propyl-8- [6- [ N-nicotinoylmethylamino) -3-pyridinyl]Xanthine;
		130)	1, 3-diethyl-8- {6- [ N- (6-chloronicotinyl) methylamino]-3-pyridyl } xanthine;
131)	1, 3-dipropyl-8- (2-chloro-6-methoxyethylamino-4-pyridyl) xanthine;
		132)	1, 3-dipropyl-8- (2-chloro-6-methylamino-4-pyridinyl) xanthine;
133)	1, 3-dipropyl-8- {2- [ N-nicotinoyl-N- (2-methoxyethyl) amino]-6-chloro-4-pyridinyl } xanthine;
		134)	1, 3-dipropyl-8- [2- (N-nicotinoyl-N-methylamino) -6-chloro-4-pyridinyl]Xanthine;
135)	1-cyclopropyl-3-propyl-8- {6- [ N- (6-chloronicotinyl) methylamino]-3-pyridyl } xanthine;
		136)	1-ethyl-3-cyclopropyl-8- (6-methylamino-3-pyridinyl) xanthine;

137)	1-ethyl-3-cyclopropyl-8- [6- (2-methoxyethyl) amino-3-pyridinyl]Xanthine;
		138)	1, 3-diethyl-8- (6-hydrazino-3-pyridyl) xanthine;
139)	1, 3-diethyl-8- [6- (cyclopropylamino) -3-pyridinyl]Xanthine;
		140)	1, 3-diethyl-8- [6- (cyclopropylmethylamino) -3-pyridinyl]Xanthine;
141)	n' - [5- (1, 3-diethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-8-yl) -pyridin-2-yl]-a hydrazide;
		142)	n- [5- (1, 3-diethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-8-yl) -pyridin-2-yl]-N' - (pyridine-3-carbonyl) -hydrazide;
143)	1, 3-diethyl-8- [6- (ethylamino) -3-pyridinyl]Xanthine;
		144)	1, 3-diethyl-8- [6- (N-nicotinoyl cyclopropylmethylamino) -3-pyridinyl]Xanthine; and
145)	1-Cyclopropylmethyl-3-ethyl-8- {6- [ N- (6-chloronicotinyl) methylamino]-3-pyridyl } xanthine.

In one aspect of the present invention, there is provided a pharmaceutical composition comprising: (a) a therapeutically effective amount of the above compound; and (b) a pharmaceutically acceptable excipient. In another aspect, there is provided a pharmaceutical composition comprising: (a) a therapeutically effective amount of the above compound; and (b) a pharmaceutically acceptable excipient.

In one aspect of the invention there is provided a therapeutic method for the prevention or treatment of a pathological condition or symptom in a mammal, wherein adenosine A is implicated_2BReceptor activity and antagonism is desired, said method comprising administering to said mammal an effective amount of a compound of the present invention. In another aspect of the invention there is provided a method of treating asthma, allergy, allergic diseases or autoimmune diseases which comprises administering to a mammal in need of such treatment an effective amount of a compound of the invention.

In one aspect of the present invention there is provided a method of treating diarrheal disease, insulin resistance, diabetes, cancer, ischemia/reperfusion injury, diabetic retinopathy or hyperbaric oxygen induced retinopathy which comprises administering to a mammal in need of such treatment an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In another aspect, a therapeutic method is provided for preventing or treating a pathological condition or symptom in a mammal, wherein adenosine A is implicated_2BReceptor activity and antagonism is desired, comprising administering to said mammal an effective amount ofThe compounds of the present invention.

In one aspect of the invention there is provided the use of a compound of the invention in medical therapy. In another aspect, there is provided the use of a compound of the invention in the manufacture of a medicament for the treatment of a disease in a mammal, such as a human.

It will be clear that any aspect or feature of the present invention, whether characterized as preferred or not, may be combined with any other aspect or feature of the present invention, whether or not such other feature is characterized as preferred. For example, an aspect or feature as preferably described, such as a particular R group or a particular R for a particular compound of formula I¹Group (e.g. wherein R¹Is hydrogen, (C)₁-C₅) Alkyl, halo (C)₁-C₈) Alkyl, (C)₃-C₅) Alkenyl or (C)₃-C₅) Alkynyl) may be combined with any other group such as R²、X、Z、Z¹Etc. are combined together to form the compounds of the invention having various combinations of substituents without departing from the invention.

Other compounds useful in the practice of the present invention are set forth in the following table:

table 1: a. the_2BActivity of antagonists

Note: +: ki < 10000nM, + +: ki < 5000nM, + + +: ki < 500nM, + ++: ki is less than 100 nM.

Synthesis of Compounds of formula I

Compounds of formula IA can be prepared by p.j.scammells et al, j.med.chem.372704-2712 (1994). The diamino-1, 3-disubstituted uracil is acylated with 6-chloronicotinyl chloride in pyridine at 5 ℃ to give the compound of formula (5 a). The resulting amide (5a) is cyclized by refluxing in an aqueous sodium hydroxide solution to give compound IA. As shown in reaction scheme 1, 6-chloronicotinoyl chloride is prepared by refluxing 6-hydroxynicotinic acid in thionyl chloride using DMF as a catalyst.

Compound IA can be alkylated with alkyl bromides or alkyl iodides to give compounds of formula IB. Compounds of formula IC are obtained by reacting compounds IA or IB with substituted amines in a pressurized tube reactor (pressurized tube) at 150 ℃ and 160 ℃. A compound of formula IC (wherein R⁴Hydrogen) can be reacted with isocyanates or acid chlorides to give compounds in which R is⁴Are each-C (O) NHR⁷(ID) or-C (O) R⁶(IE) of formula I.

Reaction scheme 1

As shown in the following reaction scheme 2, by subjecting theThe compounds of the present invention (wherein Z is-NR) can be prepared by reacting a compound with an isocyanate or an acid chloride⁴R⁵And R is⁴And R⁵Together with the atoms to which they are attached form a ring containing an NH group, such as IC or IA1) to give compounds of formulae IF and IG.

Reaction scheme 2

Scheme 3 shows that compound IA can be reacted with hydrazine or substituted hydrazines at 100-160 deg.C to give compounds of formula IA 2. A compound of formula IA2 (wherein R⁸Hydrogen) can be reacted with an acid chloride to provide compounds of formula IH and IJ. Compound IA can also be reacted with a ketone or aldehyde to provide a compound of formula IL.

Reaction scheme 3

The following abbreviations are used herein:

[¹²⁵I]ABA [¹²⁵I]N⁶- (4-aminobenzyl) -adenosine

¹²⁵I-ABOPX ¹²⁵I-3- (4-amino-3-iodobenzyl) -8-acetoxy (oxocetate) -1-propan

Yl-xanthines

AR adenosine receptors

CGS 216802- {4- [ (2-carboxyethyl) phenyl ] ethyl-amino } -5N-N-ethylcarbamoyl

Adenosine (I)

CPX 8-cyclopentyl-1, 3-dipropylxanthine

DMEM Dulbecco modified eagle medium

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

EDTA ethylenediaminetetraacetic acid (Ethylenediaminetetraacetate)

HEK cell human embryonic kidney cell

Ki equilibrium inhibition constant

NECA 5' - (N-ethylcarbamoyl) adenosine

R-PIA R-N⁶-phenylisopropyladenosine

TEA Triethylamine

TLC thin layer chromatography

ZM 2413854- (2- [ 7-amino-2- { furyl } {1, 2, 4} triazolo {2, 3-a } {1, 3, 5} tris

Oxazin-5-ylaminoethyl ] phenols

(4-(2-[7-amino-2-{furyl}{1，2，4}triazolo{2，3-a}{1，3，5}triazi

n-5-ylaminoethyl]phenol)

Where the compound is sufficiently basic or acidic to form a stable, non-toxic acid or base salt, it may be appropriate for the compound to be administered as a salt. Examples of pharmaceutically acceptable salts are, for example, the various organic acid addition salts with various acids forming physiologically acceptable anions, such as tosylate, mesylate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α -ketoglutarate and α -glycerophosphate. Various suitable inorganic salts may also be formed, including hydrochlorides, sulfates, nitrates, bicarbonates, and carbonates.

Various pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound (such as an amine) with a suitable acid to give a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of various carboxylic acids can also be prepared.

It will be apparent to those skilled in the art that the compounds of the present invention having chiral centers may exist and be resolved in both optically and racemic forms. Some compounds may exhibit polymorphism. It will be understood by those skilled in the art that the present invention also includes any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the present invention which possesses the useful properties described herein, and it is well known in the art how to prepare the various optically-active forms (e.g., by resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase). A is determined using various standard assays described herein or using other similar assays well known in the art_2BAdenosine antagonist activity is also a routine procedure.

The compounds of formula I can be formulated into pharmaceutical compositions and administered to a mammalian host (e.g., a human patient) in a variety of ways appropriate to the chosen route of administration (i.e., oral or parenteral administration, by intravenous, intramuscular, topical, inhalation, or subcutaneous routes, etc.). Exemplary various pharmaceutical compositions are disclosed in "Remington: science and Practice of pharmacy (The Science and Practice of pharmacy), "edited by a.gennaro, 20 th edition, Lippincott, Williams & Wilkins, philiadelphia, PA.

Thus, the compounds of the present invention may be administered (e.g., orally) systemically in conjunction with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. It can be placed into hard or soft shell gelatin capsules, compressed into tablets, or mixed directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage of the compositions and formulations can, of course, vary and can suitably be from about 2% to about 60% by weight of a given unit dosage form. In such therapeutically useful compositions, the amount of active compound should be such that an effective dosage level is obtained.

The tablets, troches, pills, capsules and the like may also contain the following ingredients: various binders, such as gum tragacanth, acacia, corn starch or gelatin; various excipients, such as dicalcium phosphate; disintegrating agents, such as corn starch, potato starch, alginic acid, and the like; lubricants, such as magnesium stearate; and sweetening agents, such as sucrose, fructose, lactose or aspartame, or flavouring agents, such as peppermint, oil of wintergreen or cherry flavouring. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a vegetable oil or polyethylene glycol. Various other materials may be present as coatings or to modify the physical shape of the solid unit dosage form. For example, tablets, pills or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material in preparing any unit dosage form must be pharmaceutically acceptable and substantially non-toxic at the level of amounts used. In addition, the active compounds may be incorporated into sustained release formulations and devices (devices).

The active compounds may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salt may be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof and in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical dosage forms suitable for injection or infusion may comprise sterile aqueous solutions or dispersions or sterile powders containing the active ingredient which are suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the final dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, various liquid polyethylene glycols, and the like), vegetable oils, various non-toxic glyceryl esters, and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants. The prevention of microorganisms can be brought about by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like). In many cases, it will be preferable to include various isotonic agents, for example, sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the ingredients enumerated above, as required, followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which will yield a powder of the active ingredient plus any additional desired ingredient present in the sterile-filtered solution prior to sterilization.

For topical administration, the various compounds of the present invention may be administered in pure form, i.e., in a form in which they are liquid. It is generally required to be administered to the skin in the form of a composition or formulation, along with a dermatologically acceptable carrier, which may be solid or liquid.

Useful solid carriers include various finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, various alcohols or glycols or water-alcohol/glycol blends, in which the compounds of the present invention can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Various adjuvants, such as fragrances and other antimicrobial agents, may be added to optimize various properties for a given application. The resulting liquid composition can be applied from an absorbent pad for impregnating bandages and other dressings, or sprayed onto the affected area using a pump or aerosol sprayer.

For direct application to the skin of the user, various thickening agents (e.g., synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials) may also be used in conjunction with various liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like.

Examples of various dermatological compositions that can be used to deliver a compound of formula I to the skin are well known in the art; see, for example, Jacquet et al (U.S. Pat. No. 4,608,392), Geria et al (U.S. Pat. No. 4,992,478), Smith et al (U.S. Pat. No. 4,559,157), and Wortzman (U.S. Pat. No. 4,820,508). Useful doses of the compounds of formula I can be determined by comparing their in vitro activity to their in vivo activity in animal models. Methods of extrapolating effective doses in mice and other animals to humans are well known in the art; see, for example, U.S. patent No. 4,938,949.

The concentration of the compound of formula I in a liquid composition (e.g., lotion) is generally from about 0.1 to about 25% by weight, preferably from about 0.5 to about 10% by weight. Its concentration in a semi-solid or solid composition (e.g., a gel or powder) is about 0.1 to 5% by weight, preferably about 0.5 to 2.5% by weight.

The amount of the compound or its active salt or derivative required for use in therapy will vary not only with the particular salt selected, but also with the route of administration, the nature of the condition being treated and the age and condition of the patient, and will be ultimately at the discretion of the attendant physician or clinician.

In general, however, a suitable dosage range will be from about 1.0mg/kg to about 100mg/kg, preferably from about 10mg/kg to about 75mg/kg body weight/day, more preferably from 5mg/kg to about 20mg/kg body weight/day of the recipient.

The compounds may be conveniently administered in unit dosage form, e.g., tablets, caplets, and the like; each unit dosage form contains 4-400mg, preferably 10-200mg, most preferably 20-100mg of active ingredient.

Ideally, the active ingredient is administered such that the peak plasma concentration of the active compound is from about 0.02 to about 20 μ M, preferably from about 0.1 to about 10 μ M, most preferably from about 0.5 to about 5 μ M. These concentrations can be achieved, for example, by intravenous injection of a 0.005-0.5% solution of the active ingredient or by oral administration of a pill containing from about 4 to about 400mg of the active ingredient.

The compounds of the invention may be administered by inhalation from an inhaler, insufflator, nebulizer or pressurized pack or other device for delivering an aerosol spray. The pressurized package may include a suitable propellant, such as carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by the value delivered by the dose. The inhalers, insufflators, nebulizers are described in detail in various reference books of pharmacy, such as Remington's pharmaceutical sciences, Vol.16 (1980) or Vol.18 (1990) Mack Publishing Co.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, for example, into several discrete, non-uniformly spaced administrations; such as multiple inhalations from an insufflator or by administering multiple drops into the eye.

All patents, patent applications, books, and documents referred to in this specification are herein incorporated by reference in their entirety. In any case of inconsistent front and back, the present disclosure (including any definitions therein) will prevail. The invention has been described with reference to specific and preferred embodiments and techniques. It should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

The invention will now be illustrated by the following non-limiting examples.

Examples

Pharmacology of

The compounds of the invention can be identified as A using pharmacological models well known in the art or using the experimental methods described below_2BActivity of adenosine receptor antagonists.

The method is adopted in Robeva, A. and the like,Biochem.Pharmacol.，51545-555(1996) A in rats_2BThe receptor cDNA is subcloned into the expression plasmid pDobleTrouble, which is amplified in competent cells JM109 and the plasmid DNA is extracted using a wizardMegaprep column (Promega Corporation, Madison, Wis.) in Felgner, P.L., et alProc.Natl.Acad.Sci.USA，847413-7417(1987), A is prepared by Lipofectin_2BAdenosine receptors were introduced into HEK-293 cells.

Cell culture

Transfected HEK cells at 37 ℃ temperature and 5% CO₂/95％O₂Culturing under humidity. Clones were selected by growth of cells in 0.6mg/mL G418. The transfected cells were maintained in DMEM supplemented with Hams F12 nutrient mixture (1/1), 10% newborn calf serum, 2mM glutamine and containing 50IU/mL penicillin, 50mg/mL streptomycin and 0.2mg/mL geneticin (G418, Boehringer Mannheim). Cells were cultured with a circular plate having a diameter of 10cm, and subculture was performed when the cells were confluent (after about 72 hours).

Radioligand binding studies

A_2BReceptor: confluent monolayer HEK-A_2BThe cells were washed with PBS followed by ice-cooled buffer A (10mM HEPES, 10mM EDTA, pH7.4) with various protease inhibitors (10. mu.g/mL benzamidine, 100. mu.M phenylmethylsulfonyl fluoride and 2. mu.g/mL aprotinin, 2. mu.g/mL pepstatin and 2. mu.g/mL leupeptin). Cells were lysed in polytron (brinkmann) for 20 seconds, centrifuged at 30,000Xg, and the pellet was washed twice with buffer HE (10mM HEPES, 1mM EDTA, pH7.4, with various protease inhibitors). The pellet was resuspended in buffer HE, 10% sucrose was added, aliquoted and frozen at-80 ℃. For binding assays, membranes were thawed and diluted 5-10 fold with HE to a final protein concentration of about 1 mg/mL. To determine protein concentration, membranes and bovine serum albumin standards were dissolved in 0.2% NaOH/0.01% SDS and protein was determined using fluorescamine fluorescence. Stowell, C.P., etc.,Anal.Biochem.，85，572-580(1978)。

rat A_2BA saturated binding test of adenosine receptor is carried out using³H]ZM214,385(17Ci/mmol, Tocris Cookson, BristolUK) (Ji, X., etc.,Drug Design Discov.，16216-226(1999)) or¹²⁵I-ABOPX (2200 Ci/mmol). To prepare for¹²⁵I-ABOPX, 10. mu.L of ABOPX in a 1mM solution of methanol/1M NaOH (20: 1) was added to 50. mu.L of 100mM phosphate buffer (pH 7.3). Adding 1 or 2mCi of Na¹²⁵I, then 10. mu.L of chloramine-T in 1mg/mL water was added. After incubation at room temperature for 20 minutes, the reaction was quenched by the addition of 50. mu.L of a 10mg/mL solution of sodium metabisulfite in water. The reaction mixture was separated on a C18HPLC column, eluting with a mixture of methanol and 5mM phosphate (pH 6.0). After 5 minutes of elution with 35% methanol, the methanol concentration was ramped up to 100% over 15 minutes. Eluting unreacted ABOPX in 11-12 min; eluting for 18-19 minutes¹²⁵I-ABOPX, relativeAt the beginning¹²⁵The yield of I is 50-60%.

In equilibrium binding assays¹²⁷I/¹²⁵The ratio of I-ABOPX is 10-20/1. Radioligand binding experiments in triplicate with 20-25. mu.g of membrane protein in a medium supplemented with 1U/mL adenosine deaminase and 5mM MgCl₂In a total volume of 0.1mL HE buffer. The incubation conditions were 21 ℃ for 3 hours and nonspecific binding was determined in the presence of 100. mu.M NECA. Using 0.6nM¹²⁵I-ABOPX A competition experiment was performed. The membranes were filtered through Whatman GF/C filters using a Brandel cell harvester (Gaithersburg, Md.) and ice-cooled buffer (10mM Tris, 1mM MgCl. sub.1 mM) over 15-20 seconds₂pH7.4) three times. B is calculated by Marquardt nonlinear least squares interpolation for the single-site binding model_maxAnd K_D。Marquardt，D.M.，J.Soc.Indust.Appl.Math.，11,431-441.21(1963). Such as Linden, j.,J.Cycl.Nucl.Res.，8163-172(1982) K of different compounds_iValue can be read from IC₅₀The values obtained. Data from replicate experiments are tabulated as mean ± SEM.

Other adenosine receptors: [³H]Cpx.bruns, r.f., etc.,Naunyn-Schmiedeberg′s Arch.Pharmacol.，335，59-63(1987)。¹²⁵I-ZM241385 and¹²⁵I-ABA was used to obtain samples from rats expressing recombinant rat A₁、A_2AAnd A₃Radioligand binding assay of the membrane of HEK-293 cells of AR. [³H]R-N⁶-phenylisopropyladenosine ([ 2]³H]R-PIA, Amersham, Chicago, IL) with A from rat cortical brain membrane₁Receptor binding (Schwabe, U.S. et al,Naunyn-Schmiedeberg′s Arch.Pharmacol.，313179-³H]CGS 21680(DupontNEN, Boston, MA) and A from rat striatal membranes_2AReceptor binding (Jarvis, M.F., et al,J. Pharmacol.Exp.Therap.，251888-893(1989)) were carried out according to the methods described in the literature. Preparation of the meninges (brain membrane), preincubation at 30 ℃ for 30 minutes and incubation withAdenosine deaminase (3U/mL) was present during the incubation period with the radioligand. All non-radioactive compounds were first dissolved in DMSO and diluted with buffer to final concentration, where the amount of DMSO never exceeded 2%. Incubations were terminated by rapid filtration through Whatman GF/B filters using a Brandel cell harvester (Brandell, Gaithersburg, Md.). The tube was washed 3 times with 3mL of buffer each time.

IC for each compound was adjusted within a range of 3 orders of magnitude using at least six different competitor concentrations₅₀. Such as Linden, j.,J.Cycl.Nucl.Res.，8: 163-172(1982), the IC calculated using the non-linear regression method provided in (Graph-Pad Prism, San Diego, Calif.)₅₀Conversion of the value into an apparent K_iThe value is obtained. The Hill coefficients of the test compounds range from 0.8 to 1.1.

Functional test

With no Ca content²⁺And Mg²⁺Dulbecco's Phosphate Buffered Saline (PBS) washes HEK-A that had been confluent in T75 bottles_2BCells, then in the absence of Ca²⁺And Mg²⁺Was incubated in HBSS with 0.05% trypsin and 0.53mM EDTA until the cells detached from the bottle wall. Cells were washed twice by centrifugation at 250Xg in PBS, and resuspended in 10mL of pH7.4 containing 137mM NaCl, 5mM KCl, 0.9mM MgSO₄、1.4mM CaCl₂、3mMNaHCO₃、0.6mM Na₂HPO₄、0.4mM KH₃PO₄5.6mM glucose and 10mM HEPES and Ca²⁺Sensitive fluorescent dye indo-1-AM (5. mu.M) in HBSS for 60 minutes. Cells were washed once and suspended in 25mL of dye-free HBSS supplemented with 1U/mL adenosine deaminase and allowed to stand at room temperature. 100X adenosine receptor antagonist dissolved in DMSO or other medium is added to the cells and transferred to a bath at 37 ℃ for incubation for 2 minutes. The cells (1 million in 2ml) were then transferred to a stirred cuvette maintained at 37 ℃ in an Aminco SLM8000 spectrofluorometer (SML instruments, Urbana, IL). Obtained at 400nm and 485nm (excitation, 332nm) using a 4nm slit width (slid width) recordingIndo-1 fluorescence ratio of (1). NECA was added after an equilibration period of 100 seconds.

Cyclic AMP accumulation

Cyclic AMP was produced in DMEM/HEPES buffer (DMEM with 50mM HEPES, pH7.4, 37 ℃). The cells in each well were washed with DMEM/HEPES buffer, then 100. mu.L of adenosine deaminase (final concentration of 10IU/mL, 100. mu.L of rolipram and cilostamide solutions (final concentration of 10. mu.M each) were added, followed by 50. mu.L of test compound (appropriate concentration) or buffer, 15 minutes later the incubation at 37 ℃ was terminated, the liquid was discarded, 200. mu.L of 0.1M HCl was added and the acidic extract was stored at-20 ℃ before the assay was performed, following a slightly modified assay using cAMP binding Protein (PKA) [ van der Wenden et al, 1995)]The amount of cyclic AMP is determined. The buffer for the assay was made of 150mM K₂HPO₄10mM EDTA/0.2% BSA FV, pH 7.5. Samples (20mL) were incubated at 0 ℃ for 90 min. The hatching material was filtered onto GF/C glass microfiber filters in a Brandel M-24 cell harvester. Then 2mL of 150mMK₂HPO₄The filters were washed four times with 10mM EDTA (pH7.5, 4 ℃). The filters were assayed in Packard Emulsifier Safe scintillation fluid after 2 hours of extraction.

The data obtained from the affinity assay for the compounds of the invention are reported in table 1. Wherein A is reported_2BThe data are compared with rat A expressed in HEK-293 cells_2BReceptor (rA)_2B) Binding specificity [ alpha ]¹²⁵I]Level at which ABOPX was replaced.

Synthesis and characterization

DMSO-d on a Varian-300MHz spectrometer₆Or CDCl₃Proton nmr chromatography was performed. Unless otherwise noted, chemical shifts are expressed as ppm, with tetramethylsilane chemical shift as zero, in the low field portion, or ppm relative to DMSO (2.5 ppm). Electrospray ionization (ESI) mass spectrometry was performed using a ThermoFinnigan LCQ mass spectrometer.

A Varian C185 micron analytical column (4.6 mm) is adopted150mm) TLC (silica gel 60F) in a linear gradient or isocratic solvent system (flow rate of 1ml/min)₂₅₄0.25mm, aluminum back, EM Science, Gibbstown, NJ) and HPLC (Shimadzu) judged that all xanthine derivatives were homogeneous. The solvent system used is: MeOH (0.1% formic acid) H: H₂O (0.1% formic acid). The peaks were detected by UV absorption at 232nm and 254 nm. The results of NMR and mass spectrometry are shown to be consistent with known structures.

Example 1 general procedure

Preparation of 6-chloronicotinoyl chloride:

6-Hydroxynicotinic acid (1.444g, 10.4mmol) was suspended in thionyl chloride (8 ml). DMF (0.50ml) was added. The mixture was refluxed for 2 hours. After allowing the reaction to cool, thionyl chloride was removed by a stream of nitrogen and the residue was dried under vacuum overnight and used directly in the next step.

Preparation of 1, 3-dipropyl-8- (6-chloro-3-pyridyl) xanthine (1):

6-Chloronicotinyl chloride from 6-hydroxynicotinic acid (1.44g, 10.4mmol) was added to CH₂Cl₂(20ml) the solution was added dropwise to a solution of 5, 6-diamino-1, 3-dipropyluracil (1.81g, 8mmol) in anhydrous pyridine (8.2ml) maintained at 5 ℃. The reaction was warmed to room temperature and stirred for an additional 3 hours. Water (50ml) was added to quench the reaction. The solvent evaporated to give a dark colored oil. The oil was refluxed in 2N NaOH (20ml) for 2 hours. After cooling, the pH was carefully adjusted to 7 with concentrated HCl. The resulting solid was collected and washed with water (20ml), diethyl ether (20ml) and chloroform (20ml) to give an off-white solid (1.9 g). The product was used directly in the next step without further purification.

General procedure for the reaction of 1, 3-dipropyl-8- (6-chloro-3-pyridinyl) xanthine (1) with substituted amines

Compound 1(40mg, 0.115mmol) and the corresponding substituted amine (0.5ml or 0.5g) were placed in a pressurized tubular reactor. (4ml of ethanol as solvent if the amine has a melting point above 80 ℃) is pressurizedThe tube reactor was flushed with argon, sealed and stirred at 160 ℃ for 48-60 hours. After cooling, diethyl ether (10ml) was added. The resulting solid was collected and passed through a silica gel column or preparative TLC (solvent A: CH)₂Cl₂MeOH 20: 1-10: 1 or solvent B: CH (CH)₂Cl₂MeOH/TEA (20: 1: 0.1-4: 1: 0.1) for purification.

General procedure for the preparation of urea compounds

The amino-substituted pyridine compound (IC) (10mg) was suspended in anhydrous THF (5ml) in a pressurized tubular reactor. Isocyanate (0.25ml) was added. The mixture was stirred at 90 ℃ for 48 hours. After cooling, the solvent was evaporated. The residue was purified by preparative TLC (CH)₂Cl₂MeOH: 11: 1).

General procedure for the preparation of amide compounds

The amino-substituted pyridine compound (15mg) and the desired acid chloride (4-6 equivalents) were suspended in anhydrous DMF (2 ml). Pyridine (0.1-0.15ml) was added to the mixture. The mixture was stirred at room temperature for 24 hours. Removing solvent and passing the residue through silica gel column or preparing

TLC(CH₂Cl₂MeOH: 11: 1 or ethyl acetate: hexane: MeOH: 15: 85: 5).

Preparation of 1, 3-diethyl-8- [ 6-hydrazino-3-pyridyl ] xanthine (138)

Compound 1(500mg, 1.44mmol) and hydrazine (4ml) were placed in a pressurized tubular reactor. Ethanol (30ml) was added. The pressurized tubular reactor was flushed with argon, sealed and stirred at 100-160 ℃ for 10-16 hours. After cooling, the resulting solid was collected and washed with methanol and ether to give compound 138(40 mg). The product was used directly in the next step without further purification.

General procedure for the preparation of Compounds of formula IL

Compound 138(31.5mg, 0.1mmol) was suspended in acetic acid (5ml) in a pressurized tubular reactor. Aldehyde or ketone (0.12mmol) was added. Applying pressureThe tube reactor was flushed with argon, sealed and stirred at 100-160 ℃ for 2-10 hours. After cooling, the resulting solid was collected and passed through a silica gel column or preparative TLC (CH)₂Cl₂MeOH ═ 20: 1 to 10: 1) to give the compound of formula IL.

Examples

The following compounds of the invention were prepared using the above method.

Compound 1: 1, 3-dipropyl-8- (6-chloro-3-pyridyl) xanthine

¹H NMR(DMSO，d₆)：δ0.89(m，6H)，1.59(m，2H)，1.73(m，2H)，3.88(t，2H，J＝7.2Hz)，4.00(t，2H，J＝7.2Hz)，7.68(d，1H，J＝8.4Hz)，8.50(dd，1H，J₁＝2.4Hz，J₂＝8.4Hz)，9.07(d，1H，J＝2.4Hz).

MS：m/z 348(M+H)⁺.

Compound 2: 1-propyl-3-propargyl-8- (6-chloro-3-pyridyl) xanthine

MS：m/z 316(M+H)⁺。

Compound 3: 1, 3-dipropyl-8- (6-ethylamino-3-pyridyl) xanthine

¹H NMR(DMSO，d₆)：δ0.89(m，6H)，1.14(t，3H，J＝7.2Hz)，1.56(m，2H)，1.72(m，2H)，3.33(m，2H)，3.84(t，2H，J＝7.2Hz)，3.99(t，2H，J＝7.2Hz)，6.52(d，1H，J＝8.7Hz)，7.09(t，1H)，8.00(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，8.72(d，1H，J＝2.4Hz).

MS：m/z 357(M+H)⁺，

Compound 4: 1, 3-dipropyl-8- [6- (2-hydroxyethyl) amino-3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.57(m，2H)，1.71(m，2H)，3.36(m，2H)，3.53(m，2H)，3.85(t，2H，J＝7.2Hz)，3.99(t，2H，J＝7.2Hz)，4.73(t，1H，J＝5.4Hz)，6.57(d，1H，J＝8.7Hz)，7.11(t，1H)，7.99(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，8.70(d，1H，J＝2.4Hz).

MS：m/z 373(M+H)⁺.

Compound 5: 1, 3-dipropyl-8- [6- (4-acetylpiperazinyl) -3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.84(m，6H)，1.52(m，2H)，1.68(m，2H)，2.00(s，3H)，3.52(m，8H)，3.81(t，2H，J＝7.2Hz)，3.96(t，2H，J＝7.2Hz)，6.92(d，1H，J＝8.7Hz)，8.14(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，8.79(d，1H，J＝2.4Hz).

MS：m/z 440(M+H)⁺.

Compound 6: 1, 3-dipropyl-8- [6- (benzylamino) -3-pyridyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.87(m，6H)，1.54(m，2H)，1.71(m，2H)，3.84(t，2H，J＝7.2Hz)，3.98(t，2H，J＝7.2Hz)，4.54(d，2H，J＝6.5Hz)，6.61(d，1H，J＝8.7Hz)，7.22(m，1H)，7.31(m，4H)，7.66(t，1H，J＝6.0Hz)，8.02(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，8.71(d，1H，J＝2.4Hz).

MS：m/z 419(M+H)⁺.

Compound 7: 1, 3-dipropyl-8- [6- (1-piperidinyl) -3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.63(m，10H)，3.61(t，4H，J＝5.7Hz)，3.85(t，2H，J＝7.2Hz)，4.00(t，2H，J＝7.2Hz)，6.91(d，1H，J＝9.0Hz)，8.12(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.79(d，1H，J＝2.4Hz).

MS：m/z397(M+H)⁺.

Compound 8: 1, 3-dipropyl-8- (6-pyrrolidinylpyridin-3-yl) xanthine

¹H NMR (DMSO，d₆)：δ0.88(m，6H)，1.55(m，2H)，1.73(m，2H)，1.95(m，4H)，3.43(m，4H)，3.85(t，2H，J＝7.5Hz)，4.00(t，2H，J＝7.5Hz)，6.54(d，1H，J＝9.0Hz)，8.12(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.79(d，1H，J＝2.4Hz).

MS：m/z 383(M+H)⁺.

Compound 9: 1, 3-dipropyl-8- {6- [ 4-methyl (perhydro-1, 4-diaza)-1-yl)]-3-pyridinyl } xanthines

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.56(m，2H)，1.72(m，2H)，1.88(m，2H)，2.47(m，5H)，2.60(m，2H)，3.64(t，2H.J＝6.0Hz)，3.77(m，2H)，3.85(t，2H，J＝7.2Hz)，3.99(t，2H，J＝7.2Hz)，6.73(d，1H，J＝9.0Hz)，8.12(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.78(d，1H，J＝2.4Hz).

MS：m/z 426(M+2).

Compound 10: 1, 3-dipropyl-8- (6-methylamino-3-pyridinyl) xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.56(m，2H)，1.72(m，2H)，2.81(d，3H，J＝4.5Hz)，3.85(t，2H，J＝7.5Hz)，3.99(t，2H，J＝7.5Hz)，6.52(d，1H，J＝8.7Hz)，7.08(q，1H，J＝4.5Hz)，8.01(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，8.73(d，1H，J＝2.4Hz).

MS：m/z 343(M+H)⁺.

Compound 11: 1, 3-dipropyl-8- [6- (4-methoxybenzylamino) -3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.87(m，6H)，1.59(m，2H)，1.71(m，2H)，3.71(s，3H)，3.87(t，2H，J＝7.2Hz)，3.98(t，2H，J＝7.2Hz)，4.45(d，2H，J＝6.3Hz)，6.58(d，1H，J＝9.0Hz)，6.87(d，2H，J＝8.7Hz)，7.25(d，2H，J＝8.7Hz)，7.60(t，1H)，8.01(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.71(d，1H，J＝2.4Hz).

MS：m/z 449(M+H)⁺.

Compound 12: 1, 3-dipropyl-8- [6- (3-methylpiperidino) -3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，9H)，1.14(m，1H)，1.40-1.80(m，8H)，2.55(dt，1H，J₁＝2.1Hz，J₂＝10.5Hz)，2.86(dt，1H，J₁＝2.1Hz，J₂＝10.5Hz)，3.85(t，2H，J＝7.5Hz)，4.00(t，2H，J＝7.5Hz)，4.30(d，2H，J＝13.5Hz)，6.92(d，1H，J＝9.0Hz)，8.10(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.79(d，1H，J＝2.4Hz).

MS：m/z 411(M+H)⁺.

Compound 13: 1, 3-dipropyl-8- [6- (2-hydroxypropyl) amino-3-pyridyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.87(m，6H)，1.08(d，3H，J＝6.0Hz)，1.56(m，2H)，1.72(m，2H)，3.26(m，2H)，3.77(m，1H)，3.85(t，2H，J＝7.5Hz)，3.99(t，2H，J＝7.5Hz)，4.76(d，1H，J＝4.5Hz)，6.60(d，1H，J＝9.0Hz)，7.10(t，1H，J＝6.0Hz)，7.99(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.69(d，1H，J＝2.4Hz).

MS：m/z 387(M+H)⁺.

Compound 14: 1, 3-dipropyl-8- [6- (2, 2-dimethoxyethyl) amino-3-pyridyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.56(m，2H)，1.72(m，2H)，3.29(s，6H)，3.45(t，2H，J＝5.7Hz)，3.85(t，2H，J＝7.5Hz)，3.99(t，2H，J＝7.5Hz)，4.49(t，1H，J＝5.4Hz)，6.62(d，1H，J＝9.0Hz)，7.19(t，1H，J＝5.7Hz)，8.00(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.71(d，1H，J＝2.4Hz).

MS：m/z417(M+H)⁺.

Compound 15: 1, 3-dipropyl-8- [6- (1-hydroxy-2-propyl) amino-3-pyridyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.12(d，3H，J＝6.6Hz)，1.56(m，2H)，1.74(m，2H)，3.27(m，2H)，3.46(m，1H)，3.85(t，2H，J＝7.2Hz)，3.98(t，2H，J＝7.2Hz)，4.74(t，1H，J＝5.4Hz)，6.56(d，1H，J＝9.0Hz)，6.90(d，1H，J＝7.5Hz)，7.98(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.69(d，1H，J＝2.4Hz).

MS：m/z 387(M+H)⁺.

Compound 16: 1, 3-dipropyl-8- (6-morpholino-3-pyridyl) xanthine

¹H NMR(DMSO，d₆)：δ0.87(m，6H)，1.57(m，2H)，1.73(m，2H)，3.55(m，4H)，3.69(m，4H)，3.85(t，2H，J＝7.2Hz)，3.99(t，2H，J＝7.2Hz)，6.94(d，1H，J＝9.0Hz)，8.17(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.83(d，1H，J＝2.4Hz).

MS：m/z 399(M+H)⁺.

Compound 17: 1, 3-dipropyl-8- (6-dimethylamino-3-pyridyl) xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.55(m，2H)，1.75(m，2H)，3.09(s，6H)，3.85(t，2H，J＝7.2Hz)，3.99(t，2H，J＝7.2Hz)，6.73(d，1H，J＝9.0Hz)，8.13(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.80(d，1H，J＝2.4Hz).

MS：m/z 357(M+H)⁺.

Compound 18: 1, 3-dipropyl-8- { [6- (2-hydroxyethoxy) ethylamino ] -3-pyridinyl } xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.57(m，2H)，1.72(m，2H)，3.49(m，8H)，3.85(t，2H，J＝7.5Hz)，3.99(t，2H，J＝7.5Hz)，4.59(t，1H，J＝5.4Hz)，6.58(d，1H，J＝9.0Hz)，7.15(t，1H)，8.00(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.71(d，1H，J＝2.4Hz)，13.42(s，1H).

MS：m/z 417(M+H)⁺.

Compound 19: 1, 3-dipropyl-8- [6- (piperazin-1-yl) -3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.87(m，6H)，1.56(m，2H)，1.72(m，2H)，2.78(m，4H)，3.52(m，4H)，3.85(t，2H，J＝7.5Hz)，3.99(t，2H，J＝7.5Hz)，6.88(d，1H，J＝9.0Hz)，8.13(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.80(d，1H，J＝2.4Hz).

MS：m/z 398(M+H)⁺.

Compound 20: 1, 3-dipropyl-8- [6- (2-hydroxy-2-phenylethyl) amino-3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.87(m，6H)，1.56(m，2H)，1.72(m，2H)，3.32(m，1H)，3.55(m，4H)，3.85(t，2H，J＝7.2Hz)，3.99(t，2H，J＝7.2Hz)，4.76(m，1H)，5.55(d，1H，J＝4.5Hz)，6.63(d，1H，J＝8.7Hz)，7.20-7.40(m，6H)，8.00(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，8.72(d，1H，J＝2.4Hz)，13.42(s，1H).

MS：m/z 449(M+H)⁺.

Compound 21: 1, 3-dipropyl-8- [6- (4-aminomethylbenzylamino) -3-pyridyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.86(m，6H)，1.55(m，2H)，1.71(m，2H)，3.72(s，2H)，3.84(t，2H，J＝7.2Hz)，3.97(t，2H，J＝7.2Hz)，4.50(d，1H，J＝6.0Hz)，6.57(d，1H，J＝9.0Hz)，7.27(s，4H)，7.54(t，1H，J＝6.0Hz)，8.00(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.68(d，1H，J＝2.4Hz).

MS：m/z 448(M+H)⁺.

Compound 22: 1, 3-dipropyl-8- (6-phenylamino-3-pyridyl) xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.55(m，2H)，1.76(m，2H)，3.86(t，2H，J＝7.5Hz)，4.01(t，2H，J＝7.5Hz)，6.93(m，2H)，7.29(t，2H，J＝7.8Hz)，7.68(d，2H，J＝7.8Hz)，8.19(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.87(d，1H，J＝2.4Hz)，9.45(s，1H).

MS：m/z 405(M+H)⁺.

Compound 23: 1, 3-dipropyl-8- (6-cyclopropylamino-3-pyridyl) xanthine

¹H NMR(DMSO，d₆)：δ0.44(m，2H)，0.72(m，2H)，0.87(m，6H)，1.56(m，2H)，1.72(m，2H)，2.58(m，1H)，3.85(t，2H，J＝7.5Hz)，3.99(t，2H，J＝7.5Hz)，6.66(d，1H，J＝9.0Hz)，7.36(d，1H，J＝2.7Hz)，8.10(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.74(d，1H，J＝2.4Hz).

MS：m/z 369(M+H)⁺.

Compound 24: 1, 3-dipropyl-8- [6- (6-pyridylmethylamino) -3-pyridyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.56(m，2H)，1.72(m，2H)，3.84(t，2H，J＝7.2Hz)，3.98(t，2H，J＝7.2Hz)，4.62(d，2H，J＝6.0Hz)，6.67(d，1H，J＝8.7Hz)，7.25(m，2H)，7.73(m，2H0，8.04(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，8.51(d，1H，J＝4.8Hz)，8.69(d，1H，J＝2.4Hz).

MS：m/z 420(M+H)⁺.

Compound 25: 1, 3-dipropyl-8- [6- (4-methyl-piperazin-1-yl) -3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.87(m，6H)，1.56(m，2H)，1.72(m，2H)，2.21(s，3H)，2.38(t，4H，J＝4.8Hz)，3.59(t，4H，J＝4.8Hz)，3.85(t，2H，J＝7.5Hz)，4.00(t，2H，J＝7.5Hz)，6.93(d，1H，J＝9.0Hz)，8.15(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.81(d，1H，J＝2.4Hz).

MS：m/z 412(M+H)⁺.

Compound 26: 1, 3-dipropyl-8- [6- (3-pyridylmethylamino) -3-pyridyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.87(m，6H)，1.56(m，2H)，1.71(m，2H)，3.84(t，2H，J＝7.5Hz)，3.98(t，2H，J＝7.5Hz)，4.56(d，2H，J＝5.7Hz)，6.63(d，1H，J＝8.7Hz)，7.33(dd，1H，J₁＝4.5Hz，J₂＝7.8Hz)，7.71(m，2H)，8.04(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，8.43(dd，1H，J₁＝1.8Hz，J₂＝4.5Hz)，8.55(d，1H，J＝1.8Hz)，8.71(d，1H，J＝2.4Hz).

MS：m/z 420(M+H)⁺.

Compound 27: 1, 3-dipropyl-8- [6- (2-methylbenzylamino) -3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.87(m，6H)，1.56(m，2H)，1.72(m，2H)，2.31(s，3H)，3.85(t，2H，J＝7.2Hz)，3.99(t，2H，J＝7.2Hz)，4.50(d，2H，J＝5.4Hz)，6.62(d，1H，J＝8.7Hz)，7.10-7.25(m，4H)7.51(t，1H，J＝5.4Hz)，8.01(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，8.72(d，1H，J＝2.4Hz).

MS：m/z 433(M+H)⁺.

Compound 28: 1, 3-dipropyl-8- {6- [2- (3, 4-dimethoxyphenyl) ethylamino ] -3-pyridyl } xanthine

¹H NMR(DMSO，d₆)：δ0.87(m，6H)，1.56(m，2H)，1.72(m，2H)，2.77(t，2H，J＝7.5Hz)，3.49(m，2H)，3.70(s，3H)，3.73(s，3H)，3.85(t，2H，J＝7.5Hz)，3.99(t，2H，J＝7.5Hz)，6.55(d，1H，J＝9.0Hz)，6.74(dd，1H，J₁＝1.8Hz，J₂＝8.4Hz)，6.85(m，2H)，7.17(t，1H，J＝5.4Hz).8.01(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.73(d，1H，J＝2.4Hz).

MS：m/z 493(M+H)⁺.

Compound 29: 1, 3-dipropyl-8- {6- [ (N-propylcarbamoyl) methylamino ] -3-pyridyl } xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，9H)，1.54(m，4H)，1.72(m，2H)，3.17(m，2H)，3.30(d，3H，J＝5.4Hz)，3.86(t，2H，J＝7.5Hz)，4.01(t，2H，J＝7.5Hz)，7.43(d，1H，J＝9.0Hz)，8.01(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.99(d，1H，J＝2.4Hz)，9.29(t，1H，5.4Hz).

MS：m/z 428(M+H)⁺.

Compound 30: 1, 3-dipropyl-8- [6- (3-pentylamino) -3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，12H)，1.37-1.65(m，6H)，1.72(m，2H)，3.84(m，3H)，3.98(t，2H，J＝7.2Hz)，6.54(d，1H，J＝8.7Hz)，6.90(d，1H，J＝8.4Hz)，7.96(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，8.67(d，1H，J＝2.4Hz).

MS：m/z 399(M+H)⁺.

Compound 31: 1, 3-dipropyl-8- [6- (2, 2-diphenylethylamino) -3-pyridyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.86(m，6H)，1.54(m，2H)，1.72(m，2H)，3.82-4.00(m，6H)，4.36(t，1H，J＝7.5Hz)，6.53(d，1H，J＝9.0Hz)，7.15-7.34(m，11H)，7.97(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.75(d，1H，J＝2.4Hz).

MS：m/z 509(M+H)⁺.

Compound 32: 1, 3-dipropyl-8- {6- [2- (1-ethylpyrrolidinomethylamino) ] -3-pyridinyl } xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.04(t，2H，J＝7.2Hz)，1.50-1.86(m，8H)，2.12(m，1H)，2.25(m，1H)，2.58(m，1H)，2.86(m，1H)，3.09(m，2H)，3.51(m，1H)，3.84(t，2H，J＝7.5Hz)，3.99(t，2H，J＝7.5Hz)，6.60(d，1H，J＝9.0Hz)，6.98(br，1H)，7.99(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.70(d，1H，J＝2.4Hz).

MS：m/z 440(M+H)⁺.

Compound 33: 1, 3-dipropyl-8- [6- (3-methoxybenzylamino) -3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.87(m，6H)，1.54(m，2H)，1.72(m，2H)，3.71(s，3H)，3.85(t，2H，J＝7.8Hz)，3.99(t，2H，J＝7.8Hz)，4.51(d，2H，J＝6.0Hz)，6.61(d，1H，J＝9.0Hz)，6.70-6.91(m，3H)，7.22(t，1H，J＝7.5Hz)，7.64(t，1H，J＝6.0Hz)，8.02(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.71(d，1H，J＝2.4Hz).

MS：m/z 449(M+H)⁺.

Compound 34: 1, 3-dipropyl-8- {6- [ (N-phenylcarbamoyl) methylamino ] -3-pyridyl } xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.57(m，2H)，1.75(m，2H)，3.44(s，3H)，3.86(t，2H，J＝7.5Hz)，4.02(t，2H，J＝7.5Hz)，7.04(t，1H，J＝7.2Hz)，7.32(t，2H，J＝7.5Hz)，7.48(d，1H，J＝9.0Hz)，7.60(m，3H)，8.47(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，9.12(d，1H，J＝2.4Hz).

MS：m/z 462(M+H)⁺.

Compound 35: 1, 3-dipropyl-8- [6- (furfurylamino) -3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆：δ0.88(m，6H)，1.57(m，2H)，1.73(m，2H)，3.87(t，2H，J＝7.5Hz)，3.99(t，2H，J＝7.5Hz)，4.52(d，2H，J＝5.7Hz)，6.27(d，1H，J＝3.0Hz)，6.38(m，1H)，6.3(d，1H，J＝9.0Hz)，7.56(m，2H)，8.03(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.73(d，1H，J＝2.4Hz).

MS：m/z 409(M+H)⁺.

Compound 36: 1, 3-dipropyl-8- {6- [2- (4-methoxyphenyl) ethylamino ] -3-pyridyl } xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.56(m，2H)，1.72(m，2H)，2.77(t，2H，J＝7.5Hz)，3.47(q，2H，t＝7.5Hz)，3.71(s，3H)，3.85(t，2H，J＝7.2Hz)，3.99(t，2H，J＝7.2Hz)，6.55(d，1H，J＝9.0Hz)，6.85(d，2H，J＝8.4Hz)，7.16(d，2H，J＝8.4Hz)，8.00(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.73(d，1H，J＝2.4Hz).

MS：m/z 463(M+H)⁺.

Compound 37: 1, 3-dipropyl-8- [6- (2-methoxybenzylamino) -3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.86(m，6H)，1.56(m，2H)，1.71(m，2H)，3.82(s，3H)，3.87(t，2H，J＝7.2Hz)，3.98(t，2H，J＝7.2Hz)，4.48(d，2H，J＝6.0Hz)，6.62(d，1H，J＝9.0Hz)，6.87(t，1H，J＝7.2Hz)，6.98(d，1H，J＝7.5Hz)，7.20(m，2H0，7.46(t，1H，J＝6.0Hz)，8(dd，1H，J1＝2.4Hz，J2＝9.0Hz)，8.70(d，1H，J＝2.4Hz).

MS：m/z 449(M+H)⁺.

Compound 38: 1, 3-dipropyl-8- [6- (propylamino) -3-pyridyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，9H)，1.53(m，4H)，1.72(m，2H)，3.24(q，2H，J＝6.3Hz)，3.85(t，2H，J＝7.5Hz)，3.98(t，2H，J＝7.5Hz)，6.53(d，1H，J＝8.7Hz)，7.13(t，1H，J＝5.7Hz)，7.99(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，8.70(d，1H，J＝2.4Hz).

MS：m/z 371(M+H)⁺.

Compound 39: 1, 3-dipropyl-8- [6- (cyclopentylamino) -3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.40-1.75(m，10H)，1.72(m，2H)，3.84(t，2H，J＝7.2Hz)，3.99(t，2H，J＝7.2Hz)，4.17(m，1H)，6.52(d，1H，J＝8.7Hz)，7.10(d，1H，J＝6.6Hz)，7.99(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，8.70(d，1H，J＝2.4Hz).

MS：m/z 397(M+H)⁺.

Compound 40: 1, 3-dipropyl-8- [6- (cyclohexylamino) -3-pyridyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.13-1.91(m，14H)，1.72(m，2H)，3.76(m，1H)，3.84(t，2H，J＝7.5Hz)，3.98(t，2H，J＝7.5Hz)，6.52(d，1H，J＝9.0Hz)，7.00(d，1H，J＝7.8Hz)，7.97(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.69(d，1H，J＝2.4Hz).

MS：m/z 411(M+H)⁺.

Compound 41: 1, 3-dipropyl-7-ethyl-8- (6-chloro-3-pyridyl) xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.33(t，3h，J＝7.2Hz)，1.59(m，2H)，1.73(m，2H)，3.87(t，2H，J＝7.5Hz)，3.99(t，2H，J＝7.5Hz)，7.74(d，1H，J＝8.4Hz)，8.19(dd，1H，J₁＝2.4Hz，J₂＝8.4Hz)，8.74(d，1H，J＝2.4Hz).

MS：m/z 376(M+H)⁺.

Compound 42: 1, 3-dipropyl-7- (3-fluoropropyl) -8- (6-chloro-3-pyridyl) xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.56(m，2H)，1.72(m，2H)，2.09(m，1H)，2.18(m，1H)，3.89(t，2H，J＝7.5Hz)，3.98(t，2H，J＝7.5Hz)，4.29(t，1H，J＝5.4Hz)，4.43(m，3H)，7.75(dd，1H，J1＝0.6Hz，J2＝8.4Hz)，8.19(dd，1H，J₁＝2.4Hz，J₂＝8.4Hz)，8.74(dd，1H，J₁＝0.6Hz，J₂＝2.4Hz).

MS：m/z 408(M+H)⁺.

Compound 43: 1, 3-dipropyl-7-methyl-8- (6-chloro-3-pyridyl) xanthine

¹H NMR(DMSO，d₆)：δ0.87(m，6H)，1.56(m，2H)，1.72(m，2H)，3.86(t，2H，J＝7.5Hz)，3.99(t，2H，J＝7.5Hz)，4.01(s，3H)，7.74(d，1H，J＝8.4Hz)，8.26(dd，1H，J₁＝2.4Hz，J₂＝8.4Hz)，8.82(d，1H，J＝2.4Hz).

MS：m/z 362(M+H)⁺.

Compound 44: 1, 3-dipropyl-7- (2-bromoethyl) -8- (6-chloro-3-pyridyl) xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.59(m，2H)，1.72(m，2H)，3.85(m，4H)，3.99(t，2H，J＝7.5Hz)，4.66(t，2H，J＝6.0Hz)，7.76(d，1H，J＝8.1Hz)，8.21(dd，1H，J₁＝2.7Hz，J₂＝8.1Hz)，8.76(d，1H，J＝2.7Hz).

MS：m/z 456(M+H)⁺.

Compound 45: 1, 3-dipropyl-8- [6- (2-thienylmethylamino) -3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.56(m，2H)，1.72(m，2H)，3.85(t，2H，J＝7.5Hz)，3.99(t，2H，J＝7.5Hz)，4.70(d，2H，J＝6.0Hz)，6.60(d，1H，J＝8.7Hz)，6.94-7.03(m，2H)，7.35(dd，1H，J₁＝1.5Hz，J₂＝5.1Hz)，7.70(t，1H，J＝6.0Hz)，8.04(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，8.75(d，1H，J＝2.4Hz).

MS：m/z 425(M+H)⁺.

Compound 46: 1, 3-dipropyl-8- {6- [ N- (4-methoxyphenyl-carbamoyl) methylamino ] -3-pyridinyl } xanthine

¹H NMR(DMSO，d₆)：δ0.89(m，6H)，1.56(m，2H)，1.73(m，2H)，3.43(s，3H)，3.73(s，3H)，3.87(t，2H，J＝7.2Hz)，4.02(t，2H，J＝7.2Hz)，6.89(dd，2H，J＝6.9Hz)，7.48(m，3H)，8.47(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，9.11(d，1H，J＝2.4Hz).

MS：m/z 492(M+H)⁺.

Compound 47: 1, 3-dipropyl-8- [6- (N-nicotinoylmethylamino) -3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.87(m，6H)，1.57(m，2H)，1.73(m，2H)，3.49(s，3H)，3.86(t，2H，J＝7.2Hz)，3.99(t，2H，J＝7.2Hz)，7.35(dd，1H，J₁＝7.8Hz，J₂＝7.8Hz)，7.41(d，1H，J＝8.4Hz)，7.71(dt，1H，J₁＝1.5Hz，J₂＝8.4Hz，)，8.32(dd，1H，J₁＝2.4Hz，J₂＝8.4Hz)，8.46(d，1H，J＝2.1)，8.54(dd，1H，J₁＝2.1Hz，J₂＝4.8Hz)，8.98(d，1H，J＝2.4Hz).

MS：m/z 448(M+H)⁺.

Compound 48: 1, 3-dipropyl-8- {6- [ N- (4-fluorophenylcarbamoyl) methylamino ] -3-pyridinyl } xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.57(m，2H)，1.75(m，2H)，3.44(s，3H)，3.88(t，2H，J＝7.5Hz)，4.03(t，2H，J＝7.5Hz)，7.15(t，2H，J＝8.7Hz)，7.49(d，1H，J＝9.0Hz)，7.62(m，2H)，8.47(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，9.12(d，1H，J＝2.4Hz).

MS：m/z 480(M+H)⁺.

Compound 49: 1, 3-dipropyl-8- [6- (N-isonicotinyl methylamino) -3-pyridyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.57(m，2H)，1.75(m，2H)，3.47(s，3H)，3.85(t，2H，J＝7.5Hz)，3.99(t，2H，J＝7.5Hz)，7.26(d，2H，J＝5.4Hz)，7.46(d，1H，J＝8.7Hz)，8.34(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，8.54(d，2H，J＝5.4Hz)，8.96(d，1H，J＝2.4Hz).

MS：m/z 448(M+H)⁺.

Compound 50: 1, 3-dipropyl-8- [6- (N-methoxycarbonylmethylamino) -3-pyridinyl ] xanthine

MS：m/z 401(M+H)⁺。

Compound 51: 1, 3-dipropyl-8- {6- [ N-phenylcarbamoyl-N- (2-phenylcarbamoyloxyethyl) amino ] -3-pyridinyl } xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.57(m，2H)，1.75(m，2H)，3.87(t，2H，J＝7.5Hz)，4.03(t，2H，J＝7.5Hz)，4.34(m，4H)，6.92-7.57(m，11H)，8.44(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，9.12(d，1H，J＝2.4Hz)，9.58(s(br)，1H).

MS：m/z 611(M+H)⁺.

Compound 52: 1, 3-dipropyl-8- {6- [4- (N-phenylcarbamoyl) ] piperazin-1-yl-3-pyridinyl } xanthine

¹H NMR(DMSO，d₆：δ0.88(m，6H)，1.56(m，2H)，1.73(m，2H)，3.57(m，4H)，3.67(m，4H)，3.86(t，2H，J＝7.2Hz)，4.01(t，2H，J＝7.2Hz)，6.93(t，1H，J＝7.8Hz)，6.99(d，1H，J＝9.0Hz)，7.23(t，2H，J＝7.8Hz)，7.46(d，2H，J＝7.8Hz)，8.19(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.61(s，1H)，8.85(d，1H，J＝2.4Hz).

MS：m/z 517(M+H)⁺.

Compound 53: 1, 3-dipropyl-8- {6- [4- (N-isonicotinyl) ] piperazin-1-yl-3-pyridinyl } xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.56(m，2H)，1.73(m，2H)，3.38(m，2H)，3.64(m，2H)，3.75(m，4H)，3.86(t，2H，J＝7.2Hz)，4.00(t，2H，J＝7.2Hz)，6.96(d，1H，J＝9.0Hz)，7.44(d，2H，J＝5.1Hz)，8.19(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.69(d，2H，J＝5.1Hz)，8.84(d，1H，J＝2.4Hz).

MS：m/z 503(M+H)⁺.

Compound 54: 1-propyl-3- (4-methoxyphenyl) ethyl-8- (6-chloro-3-pyridyl) xanthine

¹H NMR(DMSO，d₆)：δ0.84(t，3H，J＝7.2Hz)，1.53(m，2H)，2.93(t，2H，J＝7.2Hz)3.67(s，3H)，3.83(t，2H，J＝7.2Hz)，4.20(t，2H，J＝7.2Hz)，6.81(d，2H，J＝8.1Hz)，7.12(d，2H，J＝8.1Hz)，7.68(d，1H，J＝8.4Hz)，8.44(dd，1H，J₁＝2.4Hz，J₂＝8.4Hz)，8.98(d，1H，J＝2.4Hz

MS：m/z 440(M+H)⁺.

Compound 55: 1-propyl-3- (methoxyphenyl ethyl) -8- [6- (piperazin-1-yl) -3-pyridinyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.84(m，3H)，1.52(m，2H)，3.38(m，2H)，2.77(m，4H)，2.94(t，2H，J＝7.5Hz)，3.51(m，4H)，3.69(s，1H)，3.83(t，2H，J＝7.5Hz)，4.20(t，2H，J＝7.5Hz)，6.83(d，2H，J＝8.4Hz)，6.89(d，1H，J＝9.0Hz)，7.14(d，2H，J＝8.4Hz)，8.14(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.82(d，1H，J＝2.4Hz).

MS：m/z 490(M+H)⁺

Compound 56: 1, 3-dipropyl-8- [6- (4-pyridinylamino) -3-pyridyl ] xanthine

¹H NMR(DMSO，d₆)：δ0.87(m，6H)，1.56(m，2H)，1.74(m，2H)，3.87(t，2H，J＝7.5Hz)，4.03(t，2H，J＝7.5Hz)，6.30(d，2H，J＝7.8Hz)，7.94(d，1H，J＝8.7Hz)，8.53(d，1H，J＝7.8Hz)，8.60(dd，1H，J₁＝2.4Hz，J₂＝8.7Hz)，9.17(d，1H，J＝2.4Hz).

MS：m/z 407(M+2)⁺.

Compound 57: 1, 3-dipropyl-8- {6- [4- (N-nicotinoyl) ] piperazin-1-yl-3-pyridinyl } xanthine

¹H NMR(DMSO，d₆)：δ0.88(m，6H)，1.56(m，2H)，1.74(m，2H)，3.46-3.83(m，8H)，3.88(t，2H，J＝7.5Hz)，4.00(t，2H，J＝7.5Hz)，6.96(d，1H，J＝9.0Hz)，7.50(dd，1H，J₁＝7.8Hz，J₂＝7.8Hz)，7.89(d，J＝7.5Hz)，8.19(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.66(m，2H)，8.84(d，1H，J＝2.4Hz).

MS：m/z 503(M+H)⁺.

Compound 58: 1, 3-dipropyl-8- [6- (hexahydro-1, 4-diaza)-1-yl) -3-pyridinyl]Xanthine

¹H NMR(DMSO，d₆)：δ0.87(m，6H)，1.56(m，2H)，1.74(m，4H)，2.66(t，2H，J＝5.4Hz)，2.86(t，2H，J＝5.4Hz)，3.68(m，4H)，3.85(t，2H，J＝7.5Hz)，3.99(t，2H，J＝7.5Hz)，6.72(d，1H，J＝9.0Hz)，8.10(dd，1H，J₁＝2.4Hz，J₂＝9.0Hz)，8.77(d，1H，J＝2.4Hz).

MS：m/z 412(M+H)⁺.

Compound 59: 1, 3-diethyl-8- (6-chloro-3-pyridyl) xanthine

¹H NMR(DMSO，d₆)：δ1.14(t，3H，J＝6.9Hz)，1.26(t，3H，J＝6.9Hz)，3.94(q，2H，J＝6.9Hz)，4.09(q，2H，J＝6.9Hz)，7.68(d，1H，J＝8.4Hz)，8.46(dd，1H，J₁＝2.4Hz，J₂＝8.4Hz)，9.07(d，1H，J＝2.4Hz).

MS：m/z 320(M+H)⁺.

Compound 60: 1, 3-diethyl-8- [6- (piperazin-1-yl) -3-pyridinyl ] xanthine

MS：m/z 370(M+H)⁺。

Compound 61: 1, 3-diethyl-8- {6- [ (N-phenylcarbamoyl) methylamino ] -3-pyridinyl } xanthine

MS：m/z 434(M+H)⁺。

Compound 62: 1, 3-diethyl-8- [6- (N-nicotinoylethylamino) -3-pyridinyl ] xanthine

MS：m/z 434(M+H)⁺。

Compound 63: 1, 3-diethyl-8- (6-methylamino-3-pyridinyl) xanthine

MS：m/z 315(M+H)⁺。

Compound 64: 1, 3-diethyl-8- [6- (N-nicotinoylmethylamino) -3-pyridinyl ] xanthine

MS：m/z 420(M+H)⁺。

Compound 65: 1, 3-diethyl-8- [6- (N-nicotinoyl cyclopropylamino) -3-pyridinyl ] xanthine

MS：m/z 446(M+H)⁺。

Compound 66: 1, 3-dicyclopropylmethyl-8- (6-methylaminopyridin-3-yl) xanthines

MS：m/z 367(M+H)⁺。

Compound 67: 1-propargyl-3-methyl-8- (6-methylamino-3-pyridinyl) xanthine

MS：m/z 311(M+H)⁺。

Compound 68: 8- [6- (2, 5-diaza-bicyclo [2.2.2] oct-2-yl) -pyridin-3-yl ] -1, 3-dipropyl-3, 7-dihydro-purine-2, 6-dione

MS：m/z 410(M+H)⁺。

Compound 69: 1, 3-dicyclopropylmethyl-8- [6- (N-nicotinoylmethylamino) -3-pyridinyl ] xanthine

MS：m/z 472(M+H)⁺。

Compound 70: 1, 3-dicyclopropylmethyl-8- [6- (N-nicotinoylethylamino) -3-pyridinyl ] xanthine

MS：m/z 486(M+H)⁺。

Compound 71: 1, 3-diallyl-8- (6-methylamino-3-pyridinyl) xanthine

MS：m/z 339(M+H)⁺。

Compound 72: 1-cyclopropylmethyl-3-ethyl-8- (6-methylaminopyridin-3-yl) xanthine

MS：m/z 342(M+H)⁺。

Compound 73: 1, 3-diethyl-8- [6- (2-pyridylmethylamino) -3-pyridyl ] xanthine

MS：m/z 392(M+H)⁺。

Compound 74: 1, 3-diethyl-8- [6- (3-pyridylmethylamino) -3-pyridyl ] xanthine

MS：m/z 392(M+H)⁺。

Compound 75: 1, 3-diethyl-8- [6- (3-methoxybenzylamino) -3-pyridinyl ] xanthine

MS：m/z 421(M+H)⁺。

Compound 76: 1, 3-dipropyl-8- {6- [2- (3-pyridyl) -ethylamino ] -3-pyridyl } xanthine

MS：m/z 434(M+H)⁺。

Compound 77: 1, 3-diethyl-8- {6- [2- (3-pyridyl) -ethylamino ] -3-pyridyl } xanthine

MS：m/z 406(M+H)⁺。

Compound 78: 1, 3-dipropyl-8- {6- [2- (2-pyridyl) -ethylamino ] -3-pyridyl } xanthine

MS：m/z 434(M+H)⁺。

Compound 79: 1, 3-diethyl-8- {6- [2- (2-pyridyl) -ethylamino ] -3-pyridyl } xanthine

MS：m/z 406(M+H)⁺。

Compound 80: 1, 3-diethyl-8- (6-pyrrolidinylpyridin-3-yl) xanthines

MS：m/z 355(M+H)⁺。

Compound 81: 1, 3-diethyl-8- {6- [2- (1-pyrrolidinyl) -ethylamino ] -3-pyridinyl } xanthine

MS：m/z 398(M+H)⁺。

Compound 82: 1, 3-dipropyl-8- [6- (2-methoxyethyl) amino-3-pyridinyl ] xanthine

MS：m/z 387(M+H)⁺。

Compound 83: 1, 3-dipropyl-8- [6- (2-acetylaminoethyl) amino-3-pyridyl ] xanthine

MS：m/z 414(M+H)⁺。

Compound 84: 1, 3-diethyl-8- (6-bromo-3-pyridyl) xanthine

MS：m/z 364(M+H)⁺。

Compound 85: 1, 3-dipropyl-8- {6- [4- (2-pyridyl) -piperazin-1-yl ] -3-pyridyl } xanthine

MS：m/z 475(M+H)⁺。

Compound 86: 1, 3-diethyl-8- {6- [4- (2-pyridyl) -piperazin-1-yl ] -3-pyridyl } xanthine

MS：m/z 447(M+H)⁺。

Compound 87: 1, 3-diethyl-8- [6- (trans-2, 5-dimethylpiperazin-1-yl) -3-pyridinyl ] xanthine

MS：m/z 398(M+H)⁺

Compound 88: 1, 3-dipropyl-8- {6- [4- (2-pyrimidinyl) -piperazin-1-yl ] -3-pyridinyl } xanthine

MS：m/z 476(M+H)⁺。

Compound 89: 1, 3-diethyl-8- {6- [4- (2-pyrimidinyl) -piperazin-1-yl ] -3-pyridinyl } xanthine

MS：m/z 448(M+H)⁺。

Compound 90: 1, 3-diethyl-8- [6- (2-methoxyethyl) amino-3-pyridinyl ] xanthine

MS：m/z 359(M+H)⁺

Compound 91: 1-propargyl-3-methyl-8- (6-bromo-3-pyridyl) xanthine

MS：m/z 360(M+H)⁺。

Compound 92: 1, 3-diethyl-8- {6- [ N-nicotinoyl-N- (2-methoxyethyl) amino ] -3-pyridinyl } xanthine

MS：m/z 464(M+H)⁺。

Compound 93: 1-propargyl-3-methyl-8- [6- (2-methoxyethyl) -3-pyridinyl ] xanthine

MS：m/z 355(M+H)⁺。

Compound 94: 1, 3-diethyl-8- {6- [ N-isonicotinoyl-N- (2-methoxyethyl) amino ] -3-pyridinyl } xanthine

MS：m/z 464(M+H)⁺。

Compound 95: 1- [5- (1, 3-diethyl-2, 3, 6, 7-tetrahydro-2, 6-dioxo-1H-purin-8-yl) pyridin-2-yl ] -1- (2-methoxyethyl) -3- (pyridin-4-yl) urea

MS：m/z 479(M+H)⁺。

Compound 96: 1, 3-dimethyl-8- (6-bromo-3-pyridyl) xanthine

MS：m/z 460(M+H)⁺。

Compound 97: 1, 3-dimethyl-8- (6-methylamino-3-pyridinyl) xanthine

MS：m/z 287(M+H)⁺。

Compound 98: 1, 3-dimethyl-8- [6- (N-nicotinoylmethylamino) -3-pyridinyl ] xanthine

MS：m/z 392(M+H)⁺。

Compound 99: 1, 3-dipropyl-8- {6- [ N-nicotinoyl-N- (2-methoxyethyl) amino ] -3-pyridinyl } xanthine

MS：m/z 492(M+H)⁺。

Compound 100: 1-propargyl-3-methyl-8- {6- [ N-nicotinoyl-N- (2-methoxyethyl) amino ] -3-pyridinyl } xanthine

MS：m/z 359(M+H)⁺。

Compound 101: 1-propargyl-3-methyl-8- [6- (N-nicotinoylmethylamino) -3-pyridinyl ] xanthine

MS：m/z 416(M+H)⁺。

Compound 102: 1, 3-dipropyl-8- (2, 6-dichloro-3-pyridinyl) xanthine

MS：m/z 382(M+H)⁺。

Compound 103: 1, 3-dipropyl-8- (2, 6-dimethylamino-3-pyridyl) xanthine

MS：m/z 372(M+H)⁺。

Compound 104: 1, 3-dipropyl-8- [2, 6-bis (2-methoxyethyl) -3-pyridinyl ] xanthine

MS：m/z 460(M+H)⁺。

Compound 105: 1, 3-dipropyl-8- [2, 6-bis (N-nicotinoylmethylamino) -3-pyridinyl ] xanthine

MS：m/z 582(M+H)⁺。

Compound 106: 1, 3-dipropyl-8- [2, 6-bis (N-nicotinoyl-N-methoxyethyl) -3-pyridinyl ] xanthine

MS：m/z 670(M+H)⁺。

Compound 107: 1, 3-diethyl-8- {6- [ N- (2-pyrazinecarbonyl) methylamino ] -3-pyridinyl } xanthine

MS：m/z 421(M+H)⁺。

Compound 108: 1, 3-diethyl-8- {6- [ N- (isoxazole-5-carbonyl) methylamino ] -3-pyridinyl } xanthine

MS：m/z 410(M+H)⁺。

Compound 109: 1, 3-dipropyl-8- {6- [ N- (2-pyrazinecarbonyl) methylamino ] -3-pyridinyl } xanthine

MS：m/z 449(M+H)⁺。

Compound 110: 1, 3-dipropyl-8- {6- [ N- (isoxazole-5-carbonyl) methylamino ] -3-pyridinyl } xanthine

MS：m/z 438(M+H)⁺

Compound 111: 1, 3-dipropyl-8- {6- [ N- (5-methylisoxazol-3-yl-3-carbonyl) methylamino ] -3-pyridinyl } xanthine

MS：m/z 452(M+H)⁺。

Compound 112: 1, 3-dipropyl-8- {6- [ N- (2-chloro-6-methoxypyridinyl-4-carbonyl) -N-methylamino ] -3-pyridinyl } xanthine

MS：m/z 512(M+H)⁺。

Compound 113: 1, 3-dipropyl-8- {6- [ N- (isonicotinoyl N-oxide) -N-methylamino ] -3-pyridinyl } xanthine

MS：m/z 464(M+H)⁺。

Compound 114: 1-propyl-3- (4-methoxyphenyl) ethyl-8- (6-methylamino-3-pyridinyl) xanthine

MS：m/z 435(M+H)⁺。

Compound 115: 1, 3-diethyl-8- {6- [ N- (isonicotinoyl N-oxide) -N-methylamino ] -3-pyridinyl } xanthine

MS：m/z 436(M+H)⁺。

Compound 116: 1, 3-diallyl-8- (6-chloro-3-pyridyl) xanthine

MS：m/z 344(M+H)⁺。

Compound 117: 1-propyl-3- (4-methoxyphenyl) ethyl-8- [6- (N-nicotinoylmethylamino) -3-pyridinyl ] xanthine

MS：m/z 540(M+H)⁺

Compound 118: 1-propyl-3- (4-methoxyphenyl) ethyl-8- [6- (N- (6-chloronicotinyl) methylamino) -3-pyridinyl ] xanthine

MS：m/z 574(M+H)⁺。

Compound 119: 1, 3-diallyl-8- [6- (N-nicotinoylmethylamino) -3-pyridinyl ] xanthine

MS：m/z 444(M+H)⁺。

Compound 120: 1, 3-diallyl-8- {6- [ N- (6-chloronicotinyl) methylamino ] -3-pyridinyl } xanthine

MS：m/z 478(M+H)⁺。

Compound 121: 1, 3-dipropyl-8- [6- (N- [6- (trifluoromethyl) nicotinoyl ] methylamino) -3-pyridinyl ] xanthine

MS：m/z 516(M+H)⁺。

Compound 122: 1, 3-diethyl-8- [6- (2-hydroxy-5-methyl) benzylidenehydrazino ] -3-pyridyl ] xanthine

MS：m/z 434(M+H)⁺。

Compound 123: 1-cyclopropyl-3-propyl-8- [6- (N- [6- (trifluoromethyl) nicotinoyl ] methylamino) -3-pyridinyl ] xanthine

MS：m/z 446。

Compound 124: 1, 3-diethyl-8- [6- (bromopyridine-3-methylenehydrazino) -3-pyridyl ] xanthine

MS：m/z 483(M+H)⁺。

Compound 125: 1-cyclopropyl-3-ethyl-8- (6-methylamino-3-pyridinyl) xanthine

MS：m/z 327(M+H)⁺。

Compound 126: 1-cyclopropyl-3-propyl-8- (6-methylamino-3-pyridinyl) xanthine

MS：m/z 341(M+H)⁺。

Compound 127: 1-propyl-3-cyclopropyl-8- (6-methylamino-3-pyridinyl) xanthine

MS：m/z 341(M+H)⁺。

Compound 128: 1-cyclopropyl-3-propyl-8- [6- (2-methoxyethyl) amino-3-pyridinyl ] xanthine

MS：m/z 385(M+H)⁺。

Compound 129: 1-cyclopropyl-3-propyl-8- [6- (N-nicotinoylmethylamino) -3-pyridinyl) xanthine

MS：m/z 446(M+H)⁺。

Compound 130: 1, 3-diethyl-8- {6- [ N- (6-chloronicotinyl) methylamino ] -3-pyridinyl } xanthine

MS：m/z 454(M+H)⁺。

Compound 131: 1, 3-dipropyl-8- (2-chloro-6-methoxyethylamino-4-pyridyl) xanthine

MS：m/z 421(M+H)⁺。

Compound 132: 1, 3-dipropyl-8- (2-chloro-6-methylamino-4-pyridinyl) xanthine

MS：m/z 377(M+H)⁺。

Compound 133: 1, 3-dipropyl-8- {2- [ N-nicotinoyl-N- (2-methoxyethyl) amino ] -6-chloro-4-pyridinyl } xanthine

MS：m/z 527(M+H)⁺。

Compound 134: 1, 3-dipropyl-8- [2- (N-nicotinoyl-N-methylamino) -6-chloro-4-pyridinyl ] xanthine

MS：m/z 482(M+H)⁺。

Compound 135: 1-cyclopropyl-3-propyl-8- {6- [ N- (6-chloronicotinyl) methylamino ] -3-pyridinyl } xanthine

MS：m/z 480(M+H)⁺。

Compound 136: 1-ethyl-3-cyclopropyl-8- (6-methylamino-3-pyridinyl) xanthine

MS：m/z 327(M+H)⁺。

Compound 137: 1-ethyl-3-cyclopropyl-8- [6- (2-methoxyethyl) amino-3-pyridinyl ] xanthine

MS：m/z 371(M+H)⁺。

Compound 138: 1, 3-diethyl-8- (6-hydrazino-3-pyridyl) xanthine

MS：m/z 316(M+H)⁺。

Compound 139: 1, 3-diethyl-8- [6- (cyclopropylamino) -3-pyridinyl ] xanthine

MS：m/z 341(M+H)⁺。

Compound 140: 1, 3-diethyl-8- [6- (cyclopropylmethylamino) -3-pyridinyl ] xanthine

MS：m/z 355(M+H)⁺。

Compound 141: n' - [5- (1, 3-diethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-8-yl) -pyridin-2-yl ] -hydrazide

MS：m/z 421(M+H)⁺。

Compound 142: n- [5- (1, 3-diethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-8-yl) -pyridin-2-yl ] -N' - (pyridine-3-carbonyl) -hydrazide

MS：m/z 526(M+H)⁺。

Compound 143: 1, 3-diethyl-8- [6- (ethylamino) -3-pyridinyl ] xanthine

MS：m/z 329(M+H)⁺。

Compound 144: 1, 3-diethyl-8- [6- (N-nicotinoyl cyclopropylmethylamino) -3-pyridinyl ] xanthine

MS：m/z 460(M+H)⁺。

Compound 145: 1-cyclopropylmethyl-3-ethyl-8- {6- [ N- (6-chloronicotinyl) methylamino ] -3-pyridinyl } xanthine

MS：m/z 480(M+H)⁺。

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof:

wherein:

r is hydrogen or C₁-C₅An alkyl group;

R¹is C₃-C₆Cycloalkyl and C₃-C₆Cycloalkyl radical C₁-C₄An alkyl group;

R²is C₁-C₈Alkyl radical, C₃-C₈Alkenyl radical, C₃-C₈Alkynyl, C₃-C₈Cycloalkyl radical, C₃-C₈Cycloalkyl radical C₁-C₈Alkyl, or C₆-C₁₀Aryl radical C₁-C₈An alkyl group;

x is 3-pyridyl substituted at the 6-position by Z;

z is-NR⁴R⁵Or C₄-C₁₀Heterocyclyl, wherein said heterocyclyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: c₁-C₈An alkyl group;

each Z¹Independently is halogen;

R⁵selected from the group consisting of-C (O) R⁶、-CO₂R⁶or-C (O) NHR⁷；

R⁴Selected from hydrogen, C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Cycloalkyl radical C₁-C₈Alkyl radical, C₃-C₁₀Heterocyclyl radical C₁-C₈Alkyl radical, C₆-C₁₀Aryl radical, C₆-C₁₀Aryl radical C₁-C₈Alkyl radical, C₅-C₁₀Heteroaryl group, C₅-C₁₀Heteroaryl C₁-C₈Alkyl, - (C)₂-C₄-Y)_q-(CH₂)_2-4-X¹、-C(O)R⁶、-CO₂R⁶or-C (O) NR⁷R⁸(ii) a Or R⁴And R⁵Together with the atoms to which they are attached form a cyclic ring having 3, 4,5, 6, 7 or 8 ring atoms and optionally containing 1, 2, 3 or 4 atoms in the ring selected from the group consisting of nonperoxoxy-O-and amine-N (R)⁹) -a saturated or partially unsaturated monocyclic, bicyclic or aromatic ring of a heteroatom, wherein said ring is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: -C (O) R^aand-C (O) NR^bR^c；

Wherein R is¹、R²、R³、R⁴And R⁵The alkyl, alkenyl, cycloalkyl, alkynyl, aryl, heterocyclyl or heteroaryl groups of the group are optionally substituted with one or more substituents independently selected from: -OR^a、C₆-C₁₀Aryl, hydroxy C₁-C₈Alkyl and R^bR^cN-C₁-C₈An alkyl group;

wherein R is⁶Is C₁-C₈Alkyl or C₄-C₁₀A heteroaryl group; wherein said heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: halogen, -OR^aAnd halo C₁-C₈An alkyl group;

wherein R is⁷、R⁸And R⁹Independently is C₁-C₈Alkyl radical, R^aO-C₁-C₈Alkyl radical, C₆-C₁₀Aryl, or C₄-C₁₀Heteroaryl, wherein said heteroaryl or aryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of: halogen and-OR^a；

X¹is-OR⁶、-C(O)R⁶、-CO₂R⁶or-NR⁷R⁸；

Y is oxy-O-, thio-S-, sulfinyl-SO-, sulfonyl-S (O)₂And amine-N (R)⁹)-；

R^aIs hydrogen or C₁-C₆An alkyl group;

R^band R^cEach independently is hydrogen or C₆-C₁₀An aryl group; and

wherein n is 0, 1 or 2; and

q is 1, 2, 3 or 4.

2. The compound of claim 1, wherein R is hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, or isobutyl.

3. The compound of claim 1, wherein R is hydrogen.

4. The compound of claim 1, wherein R¹Is cyclopropyl or cyclopropylmethyl.

5. The compound of claim 1, wherein R²Is C₁-C₄Alkyl radical, C₃-C₄Alkenyl radical, C₃-C₄Alkynyl, phenyl C₁-C₄Alkyl or methoxyphenylethyl.

6. The compound of claim 1, wherein R²Is cyclopropyl or cyclopropylmethyl.

7. The compound of claim 1, wherein R²Is ethyl, n-propyl or allyl.

8. The compound of claim 1, wherein Z is-NR⁴R⁵Wherein R is⁴And R⁵As defined in claim 1.

9. The compound of claim 1, wherein R⁴Is hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₃-C₆cycloalkyl-C₁-C₄Alkyl radical, C₆-C₁₀Aryl radical, C₆-C₁₀aryl-C₁-C₄Alkyl radical, C₅-C₆Heteroaryl group, C₅-C₆heteroaryl-C₁-C₄Alkyl, -C (O) R⁶、-CO₂R⁶or-C (O) NR⁷R⁸Wherein R is⁶、R⁷And R⁸As defined in claim 1.

10. The compound of claim 1, wherein R⁴Is hydrogen, C₁-C₄Alkyl, hydroxy C₂-C₄Alkyl radical, C₃-C₆Cycloalkyl radical, C₆-C₁₀Aryl radical, C₇-C₁₀Aralkyl radical, C₅-C₆Heteroaryl, - (CH)₂-CH₂-O)_q-(CH₂-CH₂)-OR^a、-C(O)R⁶、-CO₂R⁶or-C (O) NR⁷R⁸Wherein q and R^a、R⁶、R⁷And R⁸As defined in claim 1.

11. The compound of claim 1, wherein R⁴Is hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethyl, aminomethylbenzyl, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, thienyl, -C (O) R⁶、-CO₂R⁶or-C (O) NHR⁷Wherein R is⁶And R⁷As defined in claim 1.

12. The compound of claim 1, wherein R⁴Is methyl, ethyl, cyclopropyl, cyclopropylmethyl, -C (O) R⁶、-CO₂R⁶or-C (O) NHR⁷Wherein R is⁶And R⁷As defined in claim 1.

13. The compound of claim 1, wherein R⁴And R⁵Together with the nitrogen to which they are attached is pyrrolidinyl, piperidinyl, piperazinyl, azaRadical diazaOr morpholinyl, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from: -COR^aand-CONR^bR^cWherein R is^a、R^bAnd R^cAs defined in claim 1.

14. The compound of claim 1, wherein R⁶Is C₁-C₆Alkyl or C₅-C₆Heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from: halogen, -OR^aAnd halo C₁-C₈Alkyl radical, wherein R^aAs defined in claim 1.

15. The compound of claim 1, wherein R⁶Is C₅-C₆Heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from: halogen and halogeno C₁-C₈An alkyl group.

16. The compound of claim 1, wherein R⁶Is pyridyl, optionally substituted by F, Cl, Br, I or CF₃And (4) substitution.

17. The compound of claim 1, wherein:

r is hydrogen, methyl or ethyl;

R¹is cyclopropyl or cyclopropylmethyl

R²Is methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl or n-butyl; and

R⁴is methyl, ethyl, cyclopropyl, cyclopropylmethyl and R⁵is-C (O) R⁶Wherein R is⁶Is optionally selected from 1, 2 or 3 independently from halogen and halo-C₁-C₈Alkyl-substituted heteroaryl.

18. The compound of claim 1, wherein R is hydrogen, methyl or ethyl; r¹Is cyclopropyl or cyclopropylmethyl, R²Is hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl or methoxyphenylethyl.

19. The compound of claim 1, wherein R⁶Is methyl or pyridyl, R⁷Is phenyl, fluorophenyl or methoxyphenyl.

20. The compound of claim 1, wherein:

r is hydrogen, methyl or ethyl;

R¹is cyclopropyl or cyclopropylmethyl;

R²is methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl or isobutyl; and is

Z is C₄-C₁₀Heterocyclyl, wherein said heterocyclyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: -COR^aand-CONR^bR^cWherein R is^a、R^bAnd R^cAs defined in claim 1.

21. The compound of claim 1, wherein Z is selected from the group consisting of:

22. the compound of claim 1, wherein-X (Z)¹)_n-Z is selected from the following groups:

23. the compound of claim 1, wherein R²Is n-propyl; r is hydrogen and n is 0.

24. The compound of claim 1, wherein-X(Z¹)_n-Z is selected from the following groups:

25. a pharmaceutical composition, comprising:

(a) a therapeutically effective amount of a compound of any one of claims 1-24; and

(b) a pharmaceutically acceptable excipient.

26. Use of a compound according to any one of claims 1 to 24, wherein adenosine a is implicated, for the manufacture of a medicament for the prevention or treatment of a pathological condition or symptom in a mammal_2BReceptor activity and requires antagonism.

27. Use of a compound according to any one of claims 1 to 24 for the manufacture of a medicament for the treatment of asthma, allergy, allergic disease or autoimmune disease.

28. Use of a compound according to any one of claims 1 to 24 for the manufacture of a medicament for the treatment of diarrheal disease, insulin resistance, diabetes, cancer, ischemia/reperfusion injury, diabetic retinopathy or hyperbaric oxygen induced retinopathy.