CN101274934A - Medicaments with HM74a receptor activity - Google Patents

Medicaments with HM74a receptor activity Download PDF

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CN101274934A
CN101274934A CNA2008100992548A CN200810099254A CN101274934A CN 101274934 A CN101274934 A CN 101274934A CN A2008100992548 A CNA2008100992548 A CN A2008100992548A CN 200810099254 A CN200810099254 A CN 200810099254A CN 101274934 A CN101274934 A CN 101274934A
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purine
dihydro
chloro
diketone
compound
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伊凡·L·平托
沙扎德·S·拉曼
内维尔·H·尼科尔森
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Abstract

The present invention provides therapeutically active compounds which are xanthine derivatives, processes for the manufacture of said derivatives, pharmaceutical formulations containing the active compounds and the use of the compounds in therapy, particularly in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial, having the formula (II): wherein R<1> is selected from: hydrogen and C1-4 alkyl which may be optionally substituted with one or more groups selected from CN and CF3, R<2> is selected from: C2-10 unsubstituted alkyl, C1-10 alkyl substituted with one or more groups selected from fluorine and CN, C5 alkenyl, unbranched C4 alkenyl, and C1-4 alkyl substituted with cycloalkyl, and R<3> is selected from halogen and CN.

Description

Medicine with HM74A receptor active
The application be that February 10, application number in 2005 are 200580011433.6 the applying date, denomination of invention divides an application for the application for a patent for invention of " medicine with HM74A receptor active ".
The present invention relates to therapeutical active compound for xanthine derivative, the method for preparing described derivative, contain the pharmaceutical preparation of described active compound and described compound treatment, particularly in treatment by the caused disease of HM74A receptor activation deficiency (under-activation) or benefit from purposes in the disease that activates the HM74A acceptor.
Dyslipidemia is the general designation that is used to describe individual lipoprotein abnormalities.Clinically, the main compound type that is used for the treatment of the cardiovascular disorder high-risk patient of suffering from dyslipidemia and causing thus is the special class (fibrates) of statins (statins), shellfish, bile acide binding resin and nicotinic acid.Nicotinic acid (Niacin, vitamins B) be used for the treatment of clinically the patient who suffers from multi-form dyslipidemia surpassed 40 surplus year.The main binding mode of nicotinic acid is by suppressing the triglyceride lipase (HSL) to hormone-sensitive, make blood plasma non-esterified fatty acid (NEFA) reduce, further reduce the liver fat metabolism, thereby reduced LDL and VLDL (low-density lipoprotein and vldl) output.It is believed that the VLDL level reduces can reducing cholesterol fat transfer protein (CETP) activity, causes HDL (high-density lipoprotein (HDL)) level to raise, and this may be to observe cardiovascular benefited reason.Therefore, nicotinic acid has produced very gratifying change to lipoprotein; VLDL and LDL level have been reduced and the HDL level that raise simultaneously.Confirm also that in addition nicotinic acid has the advantage of regulating disease, can alleviate the deterioration of atherosclerotic lesion and promote it to restore, and in a plurality of tests, also reduced the number of times that causes cardiovascular event.
Adopting nicotinic acid to treat viewed HSL restraining effect is to reduce by cAMP in the cell (cAMP) to regulate, and cAMP (cAMP) minimizing is what to be caused by the protein mediated adenylate cyclase enzyme inhibition of G-in the cell.Recently, the acceptor HM74 of G-albumen coupling and acceptor (the PCT patent application WO02/84298 that HM74A is nicotinic acid have been identified; People .J Biol Chem. such as Wise, 2003,278 (11), 9869-9874).The dna sequence dna of people HM74A can find in Genbank; Accession number AY148884.Other two pieces of papers have been supported above-mentioned discovery (people .Nature Medicine such as Tunaru, 2003,9 (3), people such as 352-255 and Soga .Biochem Biophys Res Commun., 2003,303 (1) 364-369), still wherein used term has nuance.In the paper of Tunaru, alleged people HM74 is actually HM74A, and in the paper of Soga, HM74b is exactly HM74A.The cell of transfection expression HM74A and/or HM74 has obtained initiation G after being exposed to nicotinic acid iThe ability of the protein mediated response of G-.In the mouse that lacks HM74A (m-PUMA-G) homologue, nicotinic acid can not reduce plasmal NE FA level.
Synthetic and disclose some xanthine derivative in the prior art.For example, EP0389282 discloses the xanthine derivative as the potential conditioning agent of cerebrovascular disorder.People such as Jacobson are at J.Med.Chem., and 1993,36, confirm among the 2639-2644 that a large amount of xanthine derivatives is adenosine receptor antagonists.
We find a class xanthine derivative at present, and it is the selective agonist of niacin receptor HM74A, thereby it is in treatment, prevention with to suppress to be activated by this receptor not enough caused disease or benefit from the disease that activates this receptor be useful.
Summary of the invention
The invention provides xanthine derivative and described derivative with therapeutic activity is treating, particularly treatment by the HM74A receptor activation not enough caused disease or benefit from purposes in the disease that activates this receptor, particularly lipid metabolism disease of described disease comprises dyslipidemia or hyperlipoproteinemia for example diabetes dyslipidemia and mixing dyslipidemia (mixed dyslipidaemia), in heart failure, hypercholesterolemia disease (hypercholesteraemia), cardiovascular disorder comprises atherosclerosis, arteriosclerosis, and hypertriglyceridemia.The compounds of this invention can also be used as coronary artery disease equally, thrombosis, stenocardia, chronic renal failure, peripheral vascular disease and apoplexy, and the therapeutical agent of the cardiovascular indications relevant with type ii diabetes, type i diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity.The compounds of this invention also can be used for treating various inflammatory diseasess or illness as described below.
Various intermediate as herein described, preparation, method and step have constituted the present invention on the other hand.
Detailed Description Of The Invention
According to an aspect of the present invention, provide the derivative of formula (I) compound and physiologic function thereof,
Figure A20081009925400051
Wherein
R 1Be selected from: hydrogen and can choosing wantonly by one or more CN of being selected from and CF 3In the C that replaces of group 1-4Alkyl;
R 2Be selected from: unsubstituted C 3-10Alkyl, the C that replaced by one or more groups that are selected among fluorine and the CN 1-10Alkyl, C 5Alkenyl, straight chain C 4Alkenyl and the C that is substituted by cycloalkyl 1-4Alkyl;
And R 3Be selected from halogen and CN;
Condition is:
(i) work as R 3Expression Cl, and R 1During the expression ethyl, R 2It or not propyl group;
(ii) work as R 3Expression Br, and R 1During the expression propyl group, R 2It or not propyl group;
(iii) work as R 3Expression Cl or Br, and R 1During the expression butyl, R 2It or not butyl; And
(iv) work as R 1Expression C 1-4Alkyl, CH 2CN or (CH 2) 3CF 3The time, R 2It or not branched-chain alkyl.
The compounds of this invention can be used for treating by the not enough caused disease of HM74A receptor activation or benefits from the disease that activates this receptor, particularly lipid metabolism disease comprises dyslipidemia or hyperlipoproteinemia for example diabetes dyslipidemia and mixing dyslipidemia, in heart failure, hypercholesterolemia disease, cardiovascular disorder comprise atherosclerosis, arteriosclerosis and hypertriglyceridemia.The compounds of this invention can also be used as coronary artery disease equally, thrombosis, stenocardia, chronic renal failure, peripheral vascular disease and apoplexy, and the therapeutical agent of the cardiovascular indications relevant with type ii diabetes, type i diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity.The compounds of this invention equally also can be as agonist or the partial agonist (HM74A conditioning agent) of HM74A.
In specific embodiments, R 1Be selected from: hydrogen, C 1-4Alkyl, CH 2CN and (CH 2) 3CF 3In a more particular embodiment, R 1Be selected from: hydrogen and methyl.
In the part embodiment, R 2Be selected from: unsubstituted C 3-10Alkyl, the C that is replaced by one or more CN substituting groups 1-6Alkyl, the C that is replaced by one or more fluoro substituents 1-10Alkyl, C 5Alkenyl, straight chain C 4Alkenyl and the C that is substituted by cycloalkyl 1-4Alkyl.Particularly, R 2Be selected from: unsubstituted C 3-10Alkyl; (CH 2) 1-5CN; The C that is replaced by one or more fluoro substituents 2-5Alkyl; C 5Alkenyl; And the C that is substituted by cycloalkyl 1-4Alkyl.More specifically, R 2Be selected from unsubstituted C 4-6Positive alkyl, for example amyl group; (CH 2) 1-3CN, for example (CH 2) CN or (CH 2) 3CN; C with one or more fluoro substituents 3-4Alkyl, particularly wherein end carbon is used the saturated C of fluorine fully 3-4Alkyl, for example (CH 2) 2-3CF 3And C 5Alkenyl particularly wherein only has the C of two keys 5Alkenyl, for example wherein double bond position in the C between the 4th and the 5th carbon 5Alkenyl (terminal alkenyl).
In specific embodiments, R 3The expression halogen.More specifically, R 3Be selected from: chlorine and bromine.The most particularly, R 3Expression chlorine.
It should be understood that any combination that the present invention includes these specific embodiments, and cover above-mentioned concrete substituent all combinations.
Concrete The compounds of this invention comprises:
(8-chloro-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl) acetonitrile,
3-butyl-8-chloro-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-1-methyl-3-amyl group-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-bromo-1-methyl-3-amyl group-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(3,3, the 3-trifluoro propyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-1-propyl group-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
3-butyl-8-chloro-1-methyl-3,7-dihydro-1H-purine-2, the 6-diketone,
(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) acetonitrile,
8-chloro-3-(2-cyclopropyl ethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-1, two (4,4,4-trifluoro butyl)-3 of 3-, 7-dihydro-1H-purine-2, the 6-diketone,
4-(8-chloro-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl) butyronitrile,
8-chloro-1-ethyl-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
1-methyl-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile,
8-chloro-3-propyl group-1-methyl-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(3-methyl butyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-amyl group-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-propyl group-3,7-dihydro-1H-purine-2, the 6-diketone,
3-butyl-1-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile,
8-chloro-3-(4-amylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-hexyl-3,7-dihydro-1H-purine-2, the 6-diketone,
4-(8-chloro-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl) butyronitrile,
8-chloro-3-hexyl-1-methyl-3,7-dihydro-1H-purine-2, the 6-diketone,
3-butyl-8-chloro-1-ethyl-3,7-dihydro-1H-purine-2, the 6-diketone,
[8-chloro-3-(2-cyclopropyl ethyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] acetonitrile,
(8-chloro-2,6-dioxo-3-propyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) acetonitrile,
8-chloro-1-(4,4,4-trifluoro butyl)-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
2,2 '-(8-chloro-2,6-dioxo-6,7-dihydro-1H-purine-1,3 (2H)-two base) diacetonitrile,
8-chloro-1-methyl-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(2-cyclohexyl ethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
1,3-dibutyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile,
1,3-dibutyl-8-iodo-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(4-methyl amyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(6-methylheptyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-octyl group-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-decyl-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(cyclohexyl methyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
(+/-)-8-chloro-3-(3-methyl amyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(2-cyclopentyl ethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(cyclopropyl methyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
(+/-)-8-chloro-3-(2-methyl butyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
(+/-)-8-chloro-3-(2-methyl amyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(cyclobutylmethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(cyclopentyl-methyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(3-cyclopropyl propyl group)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(2-cyclobutyl ethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(4-fluorine butyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(3-fluoropropyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(5-fluorine amyl group)-3,7-dihydro-1H-purine-2, the 6-diketone,
4-(8-chloro-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl) butyronitrile,
3-(the 3-butene-1-yl)-8-chloro-3,7-dihydro-1H-purine-2, the 6-diketone,
6-(8-chloro-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl)-2, the own nitrile of 2-dimethyl,
8-chloro-3-(6-fluorine hexyl)-3,7-dihydro-1H-purine-2,6-diketone.
The wording of using in the whole text in this specification sheets and claims " contains " and " comprising " and various modification thereof are meant and are included in the interior meaning.That is to say that under the situation that context allows, these wording mean that can contain other does not have clear and definite indicated element and individuality.
Term as used herein " halogen " or " halogen " are meant fluorine, chlorine, bromine and iodine.
Term as used herein " alkyl " (when the part in being used as group or group is used) is meant the straight or branched hydrocarbon chain, unless otherwise defined, is meant the straight or branched hydrocarbon chain that contains the carbon atom that specifies number.For example, C 3-C 10Alkyl is meant and contains at least 3, the straight or branched hydrocarbon chain of 10 carbon atoms at the most.The employed examples of alkyl of this paper includes but not limited to methyl (Me), ethyl (Et), n-propyl and sec.-propyl.Term " positive alkyl " specifically is meant the straight chain hydrocarbon chain.
Term as used herein " cycloalkyl " is meant the hydrocarbon ring that contains 3-6 carbon atom, do not contain heteroatoms or conjugated double bond.The example of the employed cycloalkyl of this paper includes but not limited to cyclopropyl and cyclohexyl.
Term as used herein " alkenyl " is meant the straight or branched hydrocarbon chain that contains the carbon atom that specifies number, one or more pairs of keys.
In this article, when certain group is known as by another group " replacement " or has " one or more substituting group ",, should be appreciated that described substituting group may reside on the optional position of this group unless spelt out described substituent particular location.
Any pharmaceutically acceptable derivative that term as used herein " derivative of physiologic function " is meant The compounds of this invention is its acid amides for example, comprise any pharmacologically acceptable salt of formula (I) compound and any acceptable solvent thing of formula (I) compound, after for example the people used, they can provide (directly or indirectly) formula (I) compound or its active metabolite or resistates to Mammals.It will be appreciated by one skilled in the art that and on any functional group of formula (I) compound, to modify the derivative that obtains its physiologic function, and formula (I) compound can carry out above-mentioned modification on a more than position it.
In this article, with the term " pharmaceutically acceptable " that can be included in the related use of composition (activeconstituents or vehicle) in the pharmaceutical preparation that the patient uses, be meant with this pharmaceutical preparation in can accept and the composition nontoxic aspect other any components compatibility its recipient.
Term as used herein " solvate " is meant by what the solute derivative of formula (I) compound or its salt or its physiologic function (in the present invention for) and solvent formed to have a variable stoichiometric complex compound.This kind solvent that satisfies the object of the invention can not disturb the physiologically active of described solute.Solvent for use can be an acceptable solvent.The example of suitable acceptable solvent comprises water, ethanol and acetate.The example that can use solvent is a water, and in this case, described solvate can be called the hydrate of the solute that comes into question.
Should be appreciated that for pharmaceutical application above-mentioned " salt or solvate " can be pharmacologically acceptable salt or solvate.Certainly, other salt or solvate can be used in the preparation of formula (I) compound for example or its pharmacologically acceptable salt or solvate.
Pharmacologically acceptable salt comprises Berge, Bighley and Monkhouse, J.Pharm.Sci., 1977,66, the salt described in the 1-19.Suitable pharmacologically acceptable salt comprises by adding for example an alkali metal salt that forms of alkali metal hydroxide of basic metal.The example of suitable an alkali metal salt is sodium salt or sylvite.Other suitable pharmacologically acceptable salt comprises alkaline earth salt, for example calcium salt or magnesium salts, ammonium salt; Or with the organic bases salt that forms of thanomin, trolamine, quadrol, triethylamine, choline and meglumine for example; Perhaps with the amino acid salt that forms of arginine, Methionin and Histidine for example.
Formula (I) compound is in treatment and alleviate in many lipid metabolism disease symptomses and have the potential result of treatment, described disease comprises dyslipidemia or hyperlipoproteinemia for example diabetes dyslipidemia and mixing dyslipidemia, heart failure, hypercholesterolemia disease, cardiovascular disorder comprises atherosclerosis, arteriosclerosis and hypertriglyceridemia, type ii diabetes, type i diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity.The compounds of this invention equally also can be used as the therapeutical agent of coronary artery disease, thrombosis, stenocardia, chronic renal failure, peripheral vascular disease and apoplexy.
In addition, it is believed that HM74 and HM74A acceptor and inflammation-related.Inflammation has been represented a series of blood vessels, cell and the neural response for wound.For example monocyte, neutrophilic granulocyte and granulocyte move to in-house inflammation can be described as inflammatory cell.This is accompanied by usually, and the endothelial barrier effect reduces and the interior oedema of tissue.Be commonly referred to as chronic inflammatory diseases with the inflammation of disease-related, even can continue throughout one's life.This class chronic inflammatory diseases can show by disease symptoms.Therefore, the purpose of anti-inflammatory treatment is to alleviate chronic inflammatory diseases, makes that the physiology step of healing and tissue repair is carried out.
The inflammatory diseases that The compounds of this invention was suitable for or the example of illness comprise arthritis disease or illness, particularly sacroiliitis (rheumatoid arthritis for example, osteoarthritis, pseudarthrosis malfunctioning (prostheticjoint failure)), perhaps gastrointestinal tract inflammation (ulcerative colitis for example, Crohn disease, and other inflammatory bowel and gastrointestinal illness, the gastritis and the mucosal inflammation that cause by infection, the enteropathy that causes by the non-steroid antiinflammatory drug thing), lung inflammation (adult respiratory distress syndrome for example, asthma, cystic fibrosis, or chronic obstructive pulmonary disease), heart inflammation (for example myocarditis), inflammation of neuronal tissue (for example multiple sclerosis), pancreas inflammation (for example relevant inflammation with diabetes and complication thereof, kidney inflammation (for example glomerulonephritis), chafing (dermatitis for example, psoriatic, eczema, urticaria, burn), eye inflammation (for example glaucoma), and transplant organ (for example rejection) and many organ diseases (systemic lupus erythematous for example, Sepsis) inflammation, inflammatory sequela with virus or infectation of bacteria, and the inflammation relevant with atherosclerosis and next appear at brain for example or ischemic heart disease in hypoxic or ischemia (ischaemic) wound (comprising or do not comprise perfusion again).
Specifically, The compounds of this invention can be used for treatment and preventing inflammation, diabetes and cardiovascular disorder or illness, comprises atherosclerosis, arteriosclerosis, hypertriglyceridemia and mixes dyslipidemia.
Nicotinic acid has significant side effects, and this may be to belong to its cause according to high level (the gram quantity of every day (gram quantities)) administration.Modal side effect is the intensive skin rubefaction.In certain embodiments of the invention, The compounds of this invention has side effect lower for nicotinic acid.Identified that HM74A is the high-affinity receptor of nicotinic acid, and HM74 is a low-affinity receptor.The compounds of this invention can be used as and has optionally HM74A agonist or partial agonist; Under such situation, The compounds of this invention demonstrates the higher avidity of comparison HM74 to HM74A.
The usefulness of formula (I) compound activating HM74A can adopt following enzyme and external full raji cell assay Raji to be confirmed:
Vitro test
In order to carry out transient transfection, HEK293T cell (the antigenic HEK293 cell of the big T-of stably express SV40) is remained among the DMEM that contains 10% fetus calf serum and 2mM glutamine.Cell inoculation grows to 60-80% and merges (18-24 hour) in the 90mm culture dish before transfection.With people HM74A (GenBank TMAccession number AY148884) subclone is at mammalian expression vector (pcDNA3; Invitrogen) in, use Lipofectamine reagent to carry out transfection.In order to carry out transfection, 9 μ g DNA and 30 μ l Lipofectamine are mixed among the 0.6ml Opti-MEM (LifeTechnologies Inc.), at room temperature cultivated 30 minutes, add 1.6ml Opti-MEM then.Cell is exposed to the Lipofectamine/DNA mixture following 5 hours, adds the DMEM solution of 6ml 20% (v/v) fetus calf serum then.Cell was gathered in the crops (harvested) 48 hours after transfection.By with 50ngml -1In medium, replenished 16 hours, finish the Toxins, pertussis treatment.All transient transfection research relates to acceptor and G I/oThe G Protein G O1The cotransfection of α.
In order to generate stable clone, aforesaid method is used to the CHO-K1 cell that transfection is seeded in the six hole wares and grows to 30% fusion.These cells are remained in the DMEM F-12HAM medium that contains 10% fetus calf serum and 2mM glutamine.After the transfection 48 hours, (G418 Gibco) replenishes, and carries out antibiotic tolerance cell and selects with 400 μ g/ml Geneticins with medium.After adding nicotinic acid, the clone CHO-K1 clone of stably express HM74A by [ 35S]-GTP γ S confirmed in conjunction with measuring.
P2 membrane prepare-prepare the plasma membrane that contains the P2 particulate fraction by the cell mass (cell paste) that is frozen under-80 ℃ after the results (harvest).Overall Steps carries out under 4 ℃.Cell pellet (pellet) is suspended in 10mM Tris-HCl and the 0.1mM EDTA of 1ml once more, among the pH 7.5 (buffer A), uses 20 seconds of Ultra Turrax homogenize, then by (5 times) 25-pin.With cell lysate (lysates) in Eppendorf centrifuge, 1, under the 000g centrifugal 10 minutes, make karyon and not damaged cell form bead, the P2 particulate fraction is by 16, microcentrifugation reclaimed in 30 minutes under the 000g.The P2 particulate fraction is suspended in the buffer A once more, is stored under-80 ℃ when being required.
[ 35S]-combination-(K.H. (1994) Methods Enzymol.237 3-13) measures in the 384-hole at room temperature GTP γ S for Wieland, T. and Jakobs according to previous described method.Briefly, the dilution product of preparation standard or test compounds are that 10 μ l are added in the 384-orifice plate with volume then.Film (HM74A or HM74) is diluted in assay buffer (20mM HEPES, 100mM NaCl, 10mMMgCl 2, pH7.4) in, with saponin(e (60 μ g/ml), Leadseeker WGA pearl (Amersham; 250 μ g/ holes) and 10 μ M GDP replenish, make the 20 μ l volumes that are added in each hole contain 5 μ g films.Will [ 35S]-(1170Ci/mmol, Amersham) dilution (1: 1500) adds 20 μ l to GTP γ S in each hole in assay buffer.Add after the radioligand, with the plate sealing, pulse rotation (pulse spun), and at room temperature hatched 4 hours.When incubation period, finish, at Leadseeker machine (VIEWLUX PLUS; Perkin-Elmer) read plate on, measure specificity in conjunction with level.
In vivo test
Before research, test the HM74A agonist at least 12 days the male Spague-Dawley rat (200-250g) of fasting.Compound is by intravenously (5ml/kg) or (10ml/kg) administration of per os gavage (oral gavage).Three time points before administration and after the administration (from time period of 15 minutes to 8 hours after the administration) blood sample collection (0.3ml tail vein blood).Each blood sample is transferred in the heparin test tube (BectonDickinson Microtainer, PST LH), and centrifugal (10,000g, 5 minutes) obtain plasma sample.The test kit that use is commercially available (Randox) is measured non-esterified fatty acid (NEFA) level of this plasma sample.Employing is for inhibition (with respect to the level before the administration) the expression HM74A agonist activity of plasmal NE FA level.
In order to determine whether the HM74A compound demonstrates the rubescent response relevant with nicotinic acid, and it is delivered medicine to postanesthetic cavy.Male Dunkin Hartley cavy (300-800g) is with containing vetatar (Vetalar, 40mg/kg i.m.), xylazine (Rompun, 8mg/kg i.m.) and before the mixture of vetanarcol (Sagatal, the 30mg/kg i.p.) anesthesia, fasting 12 hours.After the anesthesia, carry out tracheostomy, animal is used room air power ventilation (10-12mL/kg, 60 breaths/min).Insert conduit with the intravenous administration test compounds to jugular vein and carotid artery, collect blood then respectively.Place infrared temperature sensor (Extech Instruments) at 3-5mm place, left ear top.Before the administration test compounds 5 minutes to the administration test compounds in 40 minutes, temperature measurement result of per minute record.Automatic data collection on the Psion computer is analyzed at Excel table procedure transfer swap-in line data then.Before giving drug compound and on the frequent time point afterwards,, and be transferred in Microtainer (BD) test tube that contains Lithium heparinate (lithium heparin) by carotid artery intubate blood sample collection (0.3ml).Sample is gone up fully mixed at blood cylinder (roller), be stored on ice under 1200g centrifugal 5 minutes afterwards then.
Nicotinic acid (10mg/kg i.v.) causes and is equivalent to 10.42+1.44 (area under curve; Random cells; Average (+s.e.m.) the rising of ear temperature n=6).By contrast, the compound of embodiment 30 (10mg/kg i.v.) produces and is equivalent to 1.52+0.39 (area under curve; Random cells; Average (+s.e.m.) rising, the minimizing 85% of ear temperature n=6).
The synthetic compound (referring to following synthetic embodiment) that obtains according to formula (I), and in above-mentioned one or more described test, test.All embodiment compounds all have 4.9 (+/-0.3 log units) or higher pEC50 and 30% or higher effectiveness.Exemplified the part particular compound below.
General purifying and analytical procedure:
Mass spectrum (MS) is that [(ES+ve obtains MH using the ionizing event of electrospray anode +And M (NH 4) +Molion] or the ionizing event of electrospray negative electrode [(ES-ve obtains (M-H) -Molion] write down on the FisonsVG Platform mass spectrograph of pattern.
1H NMR spectrum is used Bmker DPX 400MHz spectrograph record, uses the tetramethyl-silicomethane as external standard.
Biotage TMChromatography is meant that device (Flash 40i or Flash 150i) that use is sold by Dyax Corporation and the post that loads with KPSil in advance carry out purifying.
The directed automated preparation of quality (Mass directed autoprep) is meant a kind of like this method: wherein material is gone up by high performance liquid chromatography, at HPLCABZ+5 μ m post (5cm x 10mm i.d.) and is used 0.1%HCO 2The aqueous solution of H and 95%MeCN, 5% water (0.5%HCO 2H) carry out purifying, adopt following condition of gradient elution: 0-1.0 minute 5%B, 1.0-8.0 minute 5 → 30%B, 8.0-8.9 minute 30%B, 8.9-9.0 minute 30 → 95%B, 9.0-9.9 minute 95%B, 9.9-10 minute 95 → 0%B, flow velocity are 8ml minute -1(system 2).Gilson 202-Fraction Collector is started by VG Platform mass spectrograph when detecting interested mass peak.
Preparation property h.p.l.c. is meant a kind of like this method: wherein material is gone up by high performance liquid chromatography, at HPLCABZ+5 μ m post (10cm x 21.2mm i.d.) and is used 0.1%HCO 2The aqueous solution of H (A) and MeCN (0.5%HCO 2H) (B) carry out purifying, adopt to have the general condition of gradient elution that following gradient system is expressed as " x to y ": 0-1.45 minute x%B, 1.45-20 minute x → y%B, 20-24 minute y → 95%B, 24-30 minute 95%B, 32-34 minute 95 → x%B, flow velocity are 8ml minute -1The Gilson233 Fraction Collector is started by UV (254nm).
SPE (Solid-Phase Extraction) is meant the post that employing is sold by International Sorbent Technology Ltd.
Strata Phenyl SPE is meant the post that use is sold by Phenomenex.Compound is seated in advance through MeCN regulates (conditioned), use on the post of aqueous equilibrium of 5%MeCN then.With compound 0.1%HCO 2The aqueous solution of H and MeCN (0.5%HCO 2H), according to suitable gradient wash-out on Combiflash Optix 10.
As implied above, discoverable type (I) compound can be used for people's medicine or veterinary drug, is used to control dyslipidemia and hyperlipoproteinemia in particular as the HM74A activator.
Therefore, the present invention provides the derivative of formula (I) compound or its physiologic function to be used for people's medicine or veterinary drug on the other hand, comprise dyslipidemia or hyperlipoproteinemia for example diabetes dyslipidemia and mixing dyslipidemia especially for treatment lipid metabolism obstacle, in heart failure, hypercholesterolemia disease, cardiovascular disorder comprises atherosclerosis, arteriosclerosis and hypertriglyceridemia, type ii diabetes, type i diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity.The compounds of this invention is provided for treatment coronary artery disease, thrombosis, stenocardia, chronic renal failure, peripheral vascular disease and apoplexy equally.
The present invention provides the derivative of formula (I) compound or its physiologic function to be used for preparation treatment lipid metabolism obstacle to comprise for example diabetes dyslipidemia and mix dyslipidemia of dyslipidemia or hyperlipoproteinemia on the other hand, in heart failure, hypercholesterolemia disease, cardiovascular disorder comprises atherosclerosis, arteriosclerosis and hypertriglyceridemia, type ii diabetes, type i diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, the medicine of obesity.The compounds of this invention is provided for treatment coronary artery disease, thrombosis, stenocardia, chronic renal failure, peripheral vascular disease and apoplexy equally.
It should be understood that herein treatment is extended comprises prevention, prevents the recurrence of symptom and inhibition and to making a definite diagnosis treatment of conditions.
According to a further aspect of the invention, provide the derivative of formula (II) compound and physiologic function thereof,
Figure A20081009925400151
Wherein:
R 1Be selected from: hydrogen and can choosing wantonly by one or more CN of being selected from and CF 3In the C that replaces of group 1-4Alkyl;
R 2Be selected from: unsubstituted C 2-10Alkyl, the C that replaced by one or more groups that are selected among fluorine and the CN 1-10Alkyl, C 5Alkenyl, straight chain C 4Alkenyl and the C that is substituted by cycloalkyl 1-4Alkyl;
And R 3Be selected from halogen and CN;
Be used for the treatment of purposes in the medicine that the lipid metabolism obstacle comprises dyslipidemia or hyperlipoproteinemia in preparation.Particularly, described purposes is used for the treatment of the diabetes dyslipidemia or mixes dyslipidemia, heart failure in preparation for formula (II) compound is provided, hypercholesterolemia disease, type ii diabetes, type i diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, stenocardia, chronic renal failure, apoplexy and cardiovascular disorder comprise the purposes in the medicine of atherosclerosis, arteriosclerosis and hypertriglyceridemia.
In one embodiment of this invention, provide formula (II) compound to be used for the treatment of the lipid metabolism obstacle and comprised dyslipidemia or hyperlipoproteinemia.Particularly, described purposes is used for the treatment of the diabetes dyslipidemia or mixes dyslipidemia, heart failure in preparation for formula (II) is provided, hypercholesterolemia disease, type ii diabetes, type i diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, stenocardia, chronic renal failure, apoplexy and cardiovascular disorder comprise the purposes in the medicine of atherosclerosis, arteriosclerosis and hypertriglyceridemia.
In specific embodiments, R 1Be selected from: hydrogen, C 1-4Alkyl, CH 2CN and (CH 2) 3CF 3In a more particular embodiment, R 1Be selected from: hydrogen and methyl.
In certain embodiments, R 2Be selected from: unsubstituted C 3-10Alkyl, the C that replaced by one or more groups that are selected among fluorine and the CN 1-10Alkyl, C 5Alkenyl, straight chain C 4Alkenyl and the C that is substituted by cycloalkyl 1-4Alkyl.Particularly, R 2Be selected from: unsubstituted C 3-10Alkyl, has the substituent C of one or more CN 1-6Alkyl, has the C of one or more fluoro substituents 1-10Alkyl, C 5Alkenyl, straight chain C 4Alkenyl and the C that is substituted by cycloalkyl 1-4Alkyl.More specifically, R 2Be selected from: unsubstituted C 3-10Alkyl; (CH 2) 1-5CN; C with one or more fluoro substituents 2-5Alkyl; C 5Alkenyl; And the C that is substituted by cycloalkyl 1-4Alkyl.The most particularly, R 2Be selected from unsubstituted C 4-6Positive alkyl, for example amyl group; (CH 2) 1-3CN, for example (CH 2) CN or (CH 2) 3CN; C with one or more fluoro substituents 3-4Alkyl, particularly wherein end carbon is used the saturated C of fluorine fully 3-4Alkyl, for example (CH 2) 2-3CF 3And C 5Alkenyl particularly wherein only has the C of two keys 5Alkenyl, for example wherein double bond position in the C between the 4th and the 5th carbon 5Alkenyl (terminal alkenyl).
In specific embodiments, R 3The expression halogen.More specifically, R 3Be selected from chlorine and bromine.The most particularly, R 3Expression chlorine.
Be used for the treatment of the lipid metabolism obstacle and comprise that dyslipidemia or hyperlipoproteinemia or preparation are used for the treatment of the particular compound that the lipid metabolism obstacle comprises the medicine of dyslipidemia or hyperlipoproteinemia and comprise:
(8-chloro-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl) acetonitrile,
3-butyl-8-chloro-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-1-methyl-3-amyl group-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-bromo-1-methyl-3-amyl group-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(3,3, the 3-trifluoro propyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-1-propyl group-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
3-butyl-8-chloro-1-methyl-3,7-dihydro-1H-purine-2, the 6-diketone,
(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) acetonitrile,
8-chloro-3-(2-cyclopropyl ethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-1, two (4,4,4-trifluoro butyl)-3 of 3-, 7-dihydro-1H-purine-2, the 6-diketone,
4-(8-chloro-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl) butyronitrile,
8-chloro-1-ethyl-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
1-methyl-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile,
8-chloro-3-propyl group-1-methyl-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(3-methyl butyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-amyl group-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-propyl group-3,7-dihydro-1H-purine-2, the 6-diketone,
3-butyl-1-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile,
8-chloro-3-(4-amylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-hexyl-3,7-dihydro-1H-purine-2, the 6-diketone,
4-(8-chloro-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl) butyronitrile,
8-chloro-3-hexyl-1-methyl-3,7-dihydro-1H-purine-2, the 6-diketone,
3-butyl-8-chloro-1-ethyl-3,7-dihydro-1H-purine-2, the 6-diketone,
[8-chloro-3-(2-cyclopropyl ethyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] acetonitrile,
(8-chloro-2,6-dioxo-3-propyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) acetonitrile,
8-chloro-1-(4,4,4-trifluoro butyl)-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
2,2 '-(8-chloro-2,6-dioxo-6,7-dihydro-1H-purine-1,3 (2H)-two base) diacetonitrile,
8-chloro-1-methyl-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(2-cyclohexyl ethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
1,3-dibutyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile,
1,3-dibutyl-8-iodo-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(4-methyl amyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(6-methylheptyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-octyl group-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-decyl-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(cyclohexyl methyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
(+/-)-8-chloro-3-(3-methyl amyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(2-cyclopentyl ethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(cyclopropyl methyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
(+/-)-8-chloro-3-(2-methyl butyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
(+/-)-8-chloro-3-(2-methyl amyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(cyclobutylmethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(cyclopentyl-methyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(3-cyclopropyl propyl group)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(2-cyclobutyl ethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(4-fluorine butyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(3-fluoropropyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-(5-fluorine amyl group)-3,7-dihydro-1H-purine-2, the 6-diketone,
4-(8-chloro-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl) butyronitrile,
3-(the 3-butene-1-yl)-8-chloro-3,7-dihydro-1H-purine-2, the 6-diketone,
6-(8-chloro-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl)-2, the own nitrile of 2-dimethyl,
8-chloro-3-(6-fluorine hexyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-chloro-3-ethyl-1-methyl-3,7-dihydro-1H-purine-2,6-diketone.
It should be understood that this aspect of the present invention comprises any combination of these specific embodiments, and cover above-mentioned concrete substituent all combinations at formula (II) compound.
In addition, the derivative that the invention provides formula (I) compound or its physiologic function is used for the treatment of arthritis disease or illness, particularly sacroiliitis (rheumatoid arthritis for example in preparation, osteoarthritis, pseudarthrosis is malfunctioning), perhaps gastrointestinal tract inflammation (ulcerative colitis for example, Crohn disease, and other inflammatory bowel and gastrointestinal illness, the gastritis and the mucosal inflammation that cause by infection, the enteropathy that causes by the non-steroid antiinflammatory drug thing), lung inflammation (adult respiratory distress syndrome for example, asthma, cystic fibrosis, or chronic obstructive pulmonary disease), heart inflammation (for example myocarditis), inflammation of neuronal tissue (for example multiple sclerosis), pancreas inflammation (for example relevant inflammation with diabetes and complication thereof, kidney inflammation (for example glomerulonephritis), chafing (dermatitis for example, psoriatic, eczema, urticaria, burn), eye inflammation (for example glaucoma), and transplant organ (for example rejection) and many organ diseases (systemic lupus erythematous for example, Sepsis) inflammation, inflammatory sequela with virus or infectation of bacteria, and the inflammation relevant with atherosclerosis and next appear at brain for example or ischemic heart disease in the medicine of hypoxic or ischemia wound (comprising or do not comprise perfusion again) in purposes.
In another or alternative aspect, provide treatment to suffer from by the not enough caused illness of HM74A receptor activation or benefit from the human or animal's of the illness that activates the HM74A acceptor method, described method comprises acceptable salt or solvate on formula (I) compound of described human or animal's object effective dosage or its physiology.
It should be understood that equally this aspect of the present invention comprises any combination of these specific embodiments, and cover above-mentioned concrete substituent all combinations at formula (I) compound.
More specifically, the invention provides treatment lipid metabolism obstacle and comprise dyslipidemia or hyperlipoproteinemia for example diabetes dyslipidemia and mixing dyslipidemia, in heart failure, hypercholesterolemia disease, cardiovascular disorder comprises atherosclerosis, arteriosclerosis and hypertriglyceridemia, type ii diabetes, type i diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, the method for obesity, described method comprise acceptable salt or solvate on formula (I) compound of described human or animal's object effective dosage or its physiology.Equally, these compounds also can be used for treating in the method for coronary artery disease, thrombosis, stenocardia, chronic renal failure, peripheral vascular disease and apoplexy, and described method comprises formula (I) compound to described human or animal's object effective dosage.
The amount that obtains the required HM74A conditioning agent of desirable biological effect depends on various factors certainly, for example the concrete clinical disease of mode of administration and recipient.In general, per daily dose can be 0.1mg-1g/kg, is generally 0.1-100mg/kg.Intravenous administration dosage can be 0.01mg-0.1g/kg for example, is generally 0.01mg-10mg/kg, and it can pass through 0.1 μ g-1mg/ minute infusion administration easily.The infusion liquid that is fit to above-mentioned purpose can contain for example 0.01 μ g-0.1mg/ milliliter.Can contain for example 0.01 μ g-1g HM74A conditioning agent in the unitary dose.Therefore, for example 0.01 μ g-0.1g can be contained in the injection ampoule, for example 0.1mg-1g can be contained in oral dosage formulation example such as tablet or the capsule.When The compounds of this invention during, do not find/anticipate toxic effect with above-mentioned dosage range administration.
The compounds of this invention itself can be used for treating by the not enough caused disease of HM74A receptor activation or benefits from the disease that activates this receptor, the example be with The compounds of this invention with can accept the form of carrier and exist with pharmaceutical preparation.Certainly, described carrier can must be acceptable aspect other components compatibility in the preparation, simultaneously must be nontoxic to the recipient.Described carrier can be that solid or liquid or both have concurrently, the HM74A conditioning agent can be prepared into the unit dose formulations form, and tablet for example wherein contains the HM74A conditioning agent of 0.05 weight %-95 weight %.
Described preparation comprises that those are fit to the preparation of oral, rectum, part, oral cavity (for example hypogloeeis) and parenteral (for example subcutaneous, intramuscular, intracutaneous or intravenously) administration.
Also providing the method for preparing this class pharmaceutical composition, described method to comprise according to the present invention mixes various compositions.
The preparation that is fit to oral administration can exist with the discrete unit form, for example contains capsule, cachet, lozenge or the tablet of the HM74A conditioning agent of predetermined amount separately; Pulvis or granule form; Solution in water or on-aqueous liquid or suspensoid form; Perhaps oil-in-water or water-in-oil emulsion form.In general, undertaken even and fine and close mixedly, then if necessary, make formed product, can prepare above-mentioned preparation like this by the solid carrier of active HM74A conditioning agent and liquid or segmentation or both are had concurrently.For example, tablet can be by preparing the powder of HM74A conditioning agent or particle and optional one or more ancillary component compactings or moulding.Compressed tablets can be by the The compounds of this invention of unrestricted flow (free-flowing) form is for example optional and (one or more) tackiness agent, lubricant, inert diluent and/or tensio-active agent and/or dispersant in suitable machine powder or particle suppress and prepare.Molded (Moulded) tablet can be by carrying out molded preparing with the wetting powder compound of inert liquid diluent in suitable machine.
For example can contain conventional excipients in the tablet of oral administration and the capsule: tackiness agent, as syrup, gum arabic, gelatin, Sorbitol Powder, tragakanta, starch mucus or polyvinylpyrrolidone; Weighting agent is as lactose, Microcrystalline Cellulose, sugar, W-Gum, calcium phosphate or Sorbitol Powder; Lubricant is as Magnesium Stearate, stearic acid, talcum, polyoxyethylene glycol or silicon-dioxide; Disintegrating agent is as yam starch, croscarmellose sodium or primojel; Perhaps wetting agent is as sodium lauryl sulphate.Tablet can be according to method dressing well known in the art.Oral liquid can be for example water-based or oiliness suspensoid, solution, emulsion, syrup or elixir form, perhaps also can be before use with the drying products form of water or other appropriate carrier reconstruct (constitution).This liquid preparation for example can contain conventional additives: suspending agent, as Sorbitol Powder syrup, methylcellulose gum, glucose/table sugar syrup, gelatin, Walocel MT 20.000PV, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible fat; Emulsifying agent is as Yelkin TTS, dehydrated sorbitol mono-fatty acid ester or gum arabic; Nonaqueous carrier (wherein can contain edible oil) is as Prunus amygdalus oil, fractionated coconut oil (fractionated coconut oil), oily ester, propylene glycol or ethanol; Perhaps sanitas is as methyl p-hydroxybenzoate or propyl ester or Sorbic Acid.If be fit to, can also contain buffering salt, seasonings, tinting material and/or sweeting agent (for example N.F,USP MANNITOL) in the preparation.
The preparation that is fit to oral cavity (hypogloeeis) administration is included in the lozenge that contains the HM74A conditioning agent in the flavoured base (being generally sucrose and gum arabic or tragakanta) and for example contains the pastille of HM74A conditioning agent in gelatin and glycerine or sucrose and the gum arabic at inert base.
The preparation of the present invention that is fit to administered parenterally generally includes the sterile aqueous preparations of HM74A conditioning agent, and described preparation can ooze with the intravital blood of expection recipient etc.These preparations can pass through intravenous administration, can also realize by subcutaneous, intramuscular or intradermal injection certainly.This class preparation usually can be by mixing HM74A conditioning agent and water, then with resulting solution sterilization and make it and blood etc. oozes and prepares.Usually contain 0.1-5%w/w HM74A conditioning agent according to Injectable composition of the present invention.
Therefore, the preparation of the present invention that contains the suitable administered parenterally of The compounds of this invention can be mixed with the form of carrying out administered parenterally by bolus injection (bolus injection) or continuous infusion, and can exist with unit dosage form, for example ampoule, bottle (vials), small volume transfusion or prefilled syringe form, perhaps the multi-dose container form with sanitas with interpolation exists.Described composition can be taked for example solution, suspensoid or the emulsion form in water or nonaqueous carrier (vehicles), and can contain various formulated for example antioxidant, buffer reagent, biocide and/or toxicity conditioning agent.Perhaps, described activeconstituents can for before using with the powder type of for example aseptic pyrogen-free water reconstruct of appropriate carrier.Described drying solid form can be by preparing aseptic the inserting in the independent sterile chamber of sterilized powder, perhaps by inserting in each container sterile solution is aseptic, and then freeze-drying and preparing.
The preparation that is fit to rectal administration can exist with the unitary dose suppository form.Described unitary dose suppository can by with HM74A conditioning agent and one or more conventional solid carriers for example cocoa butter or glyceryl ester mix, and then make resulting mixture forming and prepare.
Be fit to topical application to the preparation of skin and can take ointment, emulsion, lotion, paste, gelifying agent, sprays, aerosol or finish form.Spendable carrier comprises Vaseline, lanolin, polyoxyethylene glycol, alcohols and two or more mixture wherein.Described HM74A conditioning agent exists with the concentration that accounts for composition 0.1-15%w/w, for example 0.5-2%w/w usually.
The employed topical of this paper comprises and being blown into and inhalation.The various types of formulation examples that are used for topical comprise ointment, emulsion, lotion, pulvis, vaginal suppository, sprays, aerosol, capsule, the cartridge case that is used for sucker or insufflator or drops (for example eye drops or nasal drop).
Ointment and emulsion can add the preparation of suitable thickening material and/or jelling agent and/or solvent and obtain simultaneously by for example making use or oleaginous base.Therefore, this class matrix can for example comprise for example Albolene or vegetables oil peanut oil or Viscotrol C or solvent polyoxyethylene glycol for example for example of water and/or oil.Spendable thickening material comprises soft wax, aluminum stearate, cetostearyl alcohol, polyoxyethylene glycol, Microcrystalline Wax and beeswax.
Lotion can make use or oleaginous base preparation obtain, and in general, can also contain one or more emulsifying agents, stablizer, dispersion agent, suspending agent or thickening material.
The pulvis that is used for external application can be by means of for example talcum, lactose or the starch formation of suitable powder matrix.Drops can make use or the preparation of non-aqueous matrix obtain, and can contain one or more dispersion agents, solubilizing agent or suspending agent.
Spray composite can be formulated into aqueous pharmaceutical for example or suspensoid form or by the aerosol of sending by suitable propelling agent in the pressurized package, for example Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, 1 of propelling agent wherein, 1,1,2,3,3,3-heptafluoro-propane, 1,1,1,2-Tetrafluoroethane, carbonic acid gas or other suitable gas.
Can be mixed with and comprise for example mixture of the powder of lactose or starch of The compounds of this invention and suitable powder matrix being used for the capsule of sucker or insufflator and cartridge case (cartridges) (for example gelatin).
Can also use with other therapeutical agent combination (combination) according to pharmaceutical composition of the present invention, for example the dyslipidemia medicine (for example statins, the special class (fibrates) of shellfish, bile acide binding resin or nicotinic acid) with other type is used in combination.
The compounds of this invention can be used in combination with one or more other therapeutical agents, for example the dyslipidemia drug regimen with other type uses, as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statins) or the special class of shellfish or bile acide binding resin or nicotinic acid.Therefore the present invention provide on the other hand described combination (combination) in treatment by the not enough caused disease of HM74A receptor activation or benefit from purposes in the disease that activates this receptor, and formula (I) or (II) compound or pharmaceutically acceptable salt thereof, the derivative of solvate or physiologic function is used for combination therapy (combination therapy) lipid metabolism obstacle in preparation and comprises dyslipidemia or hyperlipoproteinemia for example diabetes dyslipidemia and mixing dyslipidemia, in heart failure, hypercholesterolemia disease, cardiovascular disorder comprises atherosclerosis, arteriosclerosis, and hypertriglyceridemia, type ii diabetes, type i diabetes, insulin resistance, hyperlipidaemia, the purposes in the medicine of anorexia nervosa or obesity.
When The compounds of this invention and other therapeutical agent were used in combination, these compounds can be by any conventional route successively or administration simultaneously.
The alleged combination in front can realize by the form of using pharmaceutical preparation easily, therefore contains aforesaid combination and optional pharmaceutically acceptable carrier or the pharmaceutical preparation of vehicle and constituted the present invention on the other hand.Independent component in the combination of this class can with separately or the pharmaceutical dosage forms that merges successively or administration simultaneously.
In the time of in being combined in same preparation, should be appreciated that these two kinds of components must be stable, and compatibility and equally can compatibility with other component in the preparation each other, and can prepare and be used for administration.When preparing respectively, they can provide with conventional formulation form (normally this area is at the known mode of this compounds) arbitrarily.
When second therapeutical agent with the antagonism same disease made up, the dosage of every kind of component can be different with the dosage that compound uses separately.Appropriate dosage can be determined by those skilled in the art easily.
Therefore, the present invention provides on the other hand and has contained formula (I) or (II) combination of acceptable salt or solvate and other therapeutic activity agent on compound or its physiology.
The alleged combination in front can realize by the form of using pharmaceutical preparation easily that the pharmaceutical preparation that therefore contains aforesaid combination and its pharmaceutically acceptable carrier has constituted the present invention on the other hand.
The compounds of this invention has useful acting duration.
The compounds of this invention and salt thereof and solvate can be according to hereinafter described method preparations, and this has constituted another aspect of the present invention.
Method A:
According to preparation of the present invention R wherein 1Be H or and R 2Identical and R 3Be the formula (I) of Cl or the method for formula (II) compound, described method comprises:
Figure A20081009925400231
I) use allyl bromide 98 alkylation guanine
Ii) use Sodium Nitrite diazotization, then hydrolysis forms xanthine again
Iii) chlorination
Iv) alkylation on the N3 and/or on N1 and N3 dialkyl groupization
V) allyl group is removed in palladium catalysis
Method B:
According to preparation of the present invention R wherein 3Be the formula (I) of CN or the method for formula (II) compound, described method comprises the step (i) and (ii) among the method A, then:
Figure A20081009925400232
Iii) alkylation on N3
Iv) alkylation on N1
V), on C8, form aldehyde by with LiHMDS lithiumation and DMF quencher
Vi) aldehyde is converted into nitrile
Vii) allyl group is removed in palladium catalysis
Method C:
According to preparation of the present invention R wherein 3Be the formula (I) of Cl or Br or the method for formula (II) compound, described method comprises the step (i)-(iv) among the method B, then:
Figure A20081009925400241
I) on C8 with NCS or NBS halogenation
Ii) allyl group is removed in palladium catalysis
Method D:
According to preparation of the present invention R wherein 3Be the formula (I) of CN or the method for formula (II) compound, described method comprises the step (i)-(iv) among the method B, then:
Figure A20081009925400242
V) form ester
The vi) hydrolysis of methyl ester
Vii) acid is converted into acid amides
Viii) acid amides is converted into nitrile
Ix) allyl group is removed in palladium catalysis
Method E:
According to preparation of the present invention R wherein 3Be the formula (I) of Cl or the method for formula (II) compound, described method comprises:
Figure A20081009925400251
I) alkylation on N3
Ii) alkylation on N1
Iii) debenzylation
Iv) chlorination on C8
Method F:
According to preparation of the present invention R wherein 1With R 2Difference and R 3Be the formula (I) of Cl or the method for formula (II) compound, described method comprises the step (i)-(iv) among the method A, then:
Figure A20081009925400252
V) alkylation on N1
Vi) allyl group is removed in palladium catalysis
Method G:
According to preparation of the present invention R wherein 1With R 2Difference and R 3Be the formula (I) of Cl or the method for formula (II) compound, described method comprises step (i) among the method F-(v) (R among the method F wherein 2Be specially SEM or MEM), then:
Figure A20081009925400261
Vi) cracking MEM or SEM blocking group
Vii) alkylation on N3, then allyl group is removed in palladium catalysis
Method H:
According to preparation of the present invention R wherein 3Be the formula (I) of Cl, Br, I or F or the method for formula (II) compound, described method comprises the step (i)-(iv) among the method B, then:
Figure A20081009925400262
V) allyl group is removed in palladium catalysis
Vi) on C8, use NCS, NBS or NIS halogenation
Method I:
According to preparation of the present invention R wherein 1Be H or alkyl, R 2Be alkyl and R 3Be the formula (I) of Cl or the method for formula (II) compound, described method comprises:
Figure A20081009925400263
I) form pyrimidine dione
Ii) nitrosylation
Iii) use Na 2S 2O 4Perhaps similarly reductive agent reduction
Iv) form xanthine
V) alkylation on N1 (choosing wantonly)
Vi) on C8, use the NCS halogenation
If be fit to or needs, as the final step in any one above-mentioned synthetic method, resulting formula (I) or formula (II) compound can be converted into acceptable salt form on the physiology, perhaps vice versa, and a kind of salt form is converted into acceptable salt form on the another kind of physiology.
Abbreviation
The THF tetrahydrofuran (THF)
The Ac ethanoyl
The DCM methylene dichloride
The improved Eagle substratum of DMEM Dulbecco
HEPES 4-(2-hydroxyethyl) piperazine-1-ethyl sulfonic acid
The DMSO methyl-sulphoxide
The NBS N-bromosuccinimide
The NCS N-chlorosuccinimide
The NIS N-iodosuccinimide
The DMF dimethyl formamide
LiHMDS hexamethyl dimethyl silanyl lithium amide
DBAD azo-2-carboxylic acid dibenzyl ester
The DIPEA diisopropyl ethyl amine
PyBOP benzotriazole-1-base oxygen base tripyrrole alkyl phosphorus
(tripyrrolidinophosphonium) hexafluorophosphate
MEM methoxy ethoxy methyl
SEM 2-(trimethyl silyl) ethoxyl methyl
The TFA trifluoroacetic acid
The RT room temperature
The △ heating
Utilize following non-limiting example that the present invention is carried out exemplary illustration:
Synthetic embodiment
Embodiment 1: 8-chloro-3-(4-amylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
A) 2-amino-7-(2-propylene-1-yl)-1,7-dihydro-6H-purine-6-one
Figure A20081009925400282
Under room temperature, nitrogen atmosphere, will contain guanosine (20g, 0.071mol), allyl bromide 98 (14.7ml, 0.169mol) and the mixture of anhydrous DMSO (100ml) stirred 18 hours.With the dense HCl of a collection of adding (50ml, 37%), mixture stirred 45 minutes after, among the impouring MeOH (600ml).This methanol solution is collected resulting white precipitate with the neutralization of 2M NaOH (aq) solution by filtering.This white solid obtains title compound (16g crude product, 119%) 50 ℃ of following vacuum-dryings 18 hours.m/z?192.2[MH +]。
B) 7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
With 2-amino-7-(2-propylene-1-yl)-1, (40g, 0.209mol) mixture in AcOH (900ml) and water (100ml) is 55 ℃ of heating down for 7-dihydro-6H-purine-6-one.Dropwise add Sodium Nitrite (57.74g, water 0.837mol) (100ml) solution.Note toxic gas.The reinforced back (about 25 minutes) that finishes, reaction mixture is cooled to envrionment temperature, is concentrated into about 1/3 of its original volume then.Add entry (500ml), resulting precipitation is collected by filtering.Resistates washes with water, uses P then under 50 ℃ 2O 5Vacuum-drying 2 hours obtains title compound (17.20g).After the moisture partial concentration, add entry (100ml).Resulting solid filters once more and is dry.Obtain more title compound (2.31g) specifically.Merge product (19.52g, 49%).m/z?193.2[MH +]。
C) 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400291
To 7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone) (10.52g, add in dry DMF 54.7mmol) (60ml) solution NCS (8.04g, 60.2mmol).Reaction mixture is nitrogen atmosphere, 20 ℃ of following stirrings 6 hours.The reaction mixture vacuum concentration obtains amber oily thing.Add MeOH, placed 18 hours.Resulting resistates filters and vacuum-drying, obtains title compound (7.69g, 62%).m/z?227.2[MH +]。
D) 8-chloro-3-(4-amylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400292
With 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (0.10g, 0.44mmol) be dissolved in and contain yellow soda ash (0.12g, 0.49mmol) and 5-bromine amylene (0.07g, among DMF 0.49mmol) (1.5ml), mixture stirring 18 hours.After alkylation finished, (0.08g 0.07mmol), continued to stir 3.5 hours to add morpholine (0.5ml) and tetrakis triphenylphosphine palladium (0).Reaction is used the washing of 2N hydrochloric acid (2x5ml) and salt solution (3x5ml) successively with ethyl acetate (10ml) dilution, separates organic phase, dry (MgSO 4) and concentrate.Crude product is suspended in the methyl alcohol (2ml), goes up purifying at aminopropyl SPE (5g) then, use methanol-eluted fractions earlier, use the methanol solution wash-out of 5% acetate again, concentrate the back and separate the title compound (0.039g, 35%) that obtains to white solid.NMR; (400MHz, d 6-DMSO) 1.75 (m, 2H), 2.05 (m, 2H), 3.85 (J=7Hz), 4.95 (m, 1H), 5.05 (m, 1H), 5.8 (m, 1H), 11.1 (br s, 1H), an exchangeable protons is not observed δ for t, 2H H13; M/z 255[MH +].
Embodiment 2: 8-chloro-3-hexyl-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400301
Use the hexyl iodide, prepare, obtain title compound according to the mode that is similar to embodiment 1.NMR; δ H(400MHz, d 6-DMSO) 0.85 (J=7Hz), 1.25 (br s, 6H), 1.6 (m, 2H), 3.85 (J=8Hz), 11.2 (br.s, 1H), an exchangeable protons is not observed δ for t, 2H for t, 3H H13; M/z 271[MH +].
Embodiment 3 and 4: (8-chloro-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl) acetonitrile and 2,2 '-(8-chloro-2,6-dioxo-6,7-dihydro-1H-purine-1,3 (2H)-two base) diacetonitrile
A) [8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-1,2,6,7-tetrahydrochysene-3H-purine-3-yl] acetonitrile and 2,2 '-[8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-6,7-dihydro-1H-purine-1,3 (2H)-two base] diacetonitrile
Figure A20081009925400303
With 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (0.445g, (0.18g, 1.7mmol) (0.1ml 1.4mmol) handles DMF 2.0mmol) (8ml) solution the 6-diketone with the bromo acetonitrile with yellow soda ash.Mixture after being mixed heated 3 hours down at 70 ℃, was cooled to 50 ℃ then, and (0.06ml 0.8mmol) handles further to use the bromo acetonitrile.Mixture continues down to keep 2 hours at 50 ℃, is cooled to envrionment temperature then and is evaporated to dried.Resistates is handled with 1M aqueous hydrochloric acid (20ml), and extracts with ethyl acetate (2x50ml).Merge organic moiety, use dried over mgso, filter and evaporation.Resistates is dissolved in the methylene dichloride (2ml), after 20 minutes, leaches the precipitated solid (unreacted 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone) of generation, further uses washed with dichloromethane.Behind the filtrate vacuum concentration, handle through flash chromatography, using gradient elution is that ethyl acetate/cyclohexane give of 1: 3 to 4: 1 is eluent.Obtain two title compounds:
[8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-1,2,6,7-tetrahydrochysene-3H-purine-3-yl] acetonitrile
White solid (0.084g, 16%); M/z 266[MH +].
2,2 '-[8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-6,7-dihydro-1H-purine-1,3 (2H)-two base] diacetonitrile
White solid (0.195g, 32%); M/z 305[MH +].
B) (8-chloro-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl) acetonitrile
(0.084g, THF 0.32mmol) (5ml) solution is by applying vacuum and nitrogen pressure is removed gas to reaction mixture continuously with [8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-1,2,6,7-tetrahydrochysene-3H-purine-3-yl] acetonitrile.Solution use successively morpholine (0.3ml, 3.4mmol) and tetrakis triphenylphosphine palladium (0) (0.03g 0.03mmol) handles.After 2 hours, mixture is handled with 2M aqueous hydrochloric acid (3ml) and chloroform (5ml).After the mixture separation, the evaporation organic phase.Product obtains the title compound (0.018g, 25%) into white solid by functional quality orientation (mass-directed) HPLC purifying in the resistates.NMR?δ H(400MHz，d 6-DMSO)4.95(s，2H)，11.49(s，1H)，14.63(br.s，1H)；m/z?226[MH +]。
C) 2,2 '-(8-chloro-2,6-dioxo-6,7-dihydro-1H-purine-1,3 (2H)-two base) diacetonitrile
Figure A20081009925400312
Use synthetic (8-chloro-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl) the described condition of acetonitrile, by 2,2 '-[8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-6,7-dihydro-1H-purine-1,3 (2H)-two base] diacetonitrile prepares title compound.Obtain title compound 0.06g (4%) for white solid; NMR δ H(400MHz, d 6-DMSO) 4.88 (s, 2H), 5.06 (s, 2H), NH does not observe δ H14; M/z 282[MNH 4 +].
Embodiment 5: 8-chloro-3-(3,3, the 3-trifluoro propyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400321
Use 3-bromo-1,1,1-trifluoro propane prepares according to the mode that is similar to embodiment 3 as alkylating reagent, obtains title compound.
NMR?δ H(400MHz，d 6-DMSO)2.64-2.76(m，2H)，4.12(t，2H，J＝7Hz)，11.30(s，1H)，14.46(br.s，1H)；m/z?283[MH +]。
Embodiment 6: 8-chloro-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400322
Use 2-bromo-1,1, the 1-Halothane, prepares according to the mode that is similar to embodiment 3 as alkali as alkylating reagent and sodium bicarbonate, obtains title compound.
δ H(400MHz，d 4-MeOD)4.68(q，2H，J＝8.5Hz)；m/z?267.1[M-H] -。
Embodiment 7 and 8: 8-chloro-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2,6-diketone and 8- Chloro-1, two (4,4,4-trifluoro butyl)-3 of 3-, 7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400323
A) 8-chloro-7-(2-propylene-1-yl)-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2,6-diketone and 8-chloro-7-(2-propylene-1-yl)-1, two (4,4,4-trifluoro butyl)-3 of 3-, 7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400331
With 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (1.5g, 6.64mmol), yellow soda ash (844mg, 7.9mmol) and 4-bromo-1,1, (1.39g 7.3mmol) stirred 7 days in dimethyl formamide (25ml, drying) 1-trifluoro butane.Reaction mixture distributes between ethyl acetate and water.Organic phase is separated back hydrochloric acid (2N), salt water washing, dry (MgSO 4) and be evaporated to dried.Crude product grinds with ether, and solid by filtration is collected, and obtains 8-chloro-7-(2-propylene-1-the yl)-3-(4,4,4-trifluoro butyl)-3 into white solid, 7-dihydro-1H-purine-2,6-diketone (1.23g, 57%).m/z?337[MH +]。
Filtrate after concentrating is gone up chromatography at silicon-dioxide, SPE post (20g).Use hexanaphthene: ethyl acetate (10: 1 to 2: 1) wash-out obtains the 8-chloro-7-(2-propylene-1-yl)-1 into soup compound, two (4,4,4-trifluoro butyl)-3 of 3-, 7-dihydro-1H-purine-2,6-diketone (480mg, 16%).m/z?447[MH +]。
B) 8-chloro-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400332
With 8-chloro-7-(2-propylene-1-yl)-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2, and the 6-diketone (84mg, 0.25mmol) and morpholine (220 μ l, 2.5mmol) degasification in tetrahydrofuran (THF) (3ml) of usefulness nitrogen, (29mg, 0.025mmol), reaction is at room temperature stirred and is spent the night to add tetrakis triphenylphosphine palladium (0) then.Collect white precipitate by filtering,, obtain the alkylbenzyldimethylasaltsum saltsum (59mg) of title compound with tetrahydrofuran (THF) and ether washing.It is handled with 2N HCl and methyl alcohol, and solvent evaporation is dissolved among the DMSO/MeOH then again to doing, and by preparation property HPLC purifying, uses the 10-40% gradient elution, obtains title compound (11mg, 14.9%).NMR?δ H(400MHz，d 4-MeOD)1.92-2.03(m，2H)，2.19-2.33(m，2H)，4.06(t，2H，J＝7Hz)；m/z?297[MH +]。
C) the 8-chloro-1, two (4,4,4-trifluoro butyl)-3 of 3-, 7-dihydro-1H-purine-2,6-diketone
With 8-chloro-7-(2-propylene-1-yl)-1,3-two (4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2,6-diketone (478mg, 1.1mmol) and morpholine (937 μ l, 11mmol) usefulness nitrogen degasification in tetrahydrofuran (THF) (10ml) adds tetrakis triphenylphosphine palladium (0) (123mg then, 0.11mmol), reaction is at room temperature stirred and is spent the night.Reaction mixture distributes between methylene dichloride and hydrochloric acid 2N.After organic phase is separated, concentrate and obtain crude product.It by aminopropyl SPE (5g) purifying, then by the acetonitrile recrystallization, is obtained title compound (75.5mg, 16.9%).NMR.δ H(400MHz，CDCl 3)1.96-2.13(m，4H)，2.15-2.29(m，4H)，4.15-4.23(m，4H)，12.94(br.s，1H)；m/z?407[MH +]。
Embodiment 9: 8-chloro-3-(2-cyclopropyl ethyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400342
A) 8-chloro-3-(2-cyclopropyl ethyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400343
With 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (1.5g, 6.64mmol), yellow soda ash (844mg, 7.9mmol) and methylsulfonic acid 2-cyclopropyl ethyl ester (1.19g 7.3mmol) stirred 2 days in the dimethyl formamide under 80 ℃ (25ml, anhydrous).Reaction mixture distributes between ethyl acetate and water.After organic phase is separated, with hydrochloric acid (2N), salt water washing, dry (MgSO 4) and be evaporated to dried.Crude product grinds with ether, by solid collected by filtration, obtains the title compound (0.96g, 49%) into white solid.m/z?295[MH +]。
B) 8-chloro-3-(2-cyclopropyl ethyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400351
With 8-chloro-3-(2-cyclopropyl ethyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (74mg, 0.25mmol) and morpholine (220 μ l, 2.5mmol) degasification in tetrahydrofuran (THF) (3ml) of usefulness nitrogen, (29mg, 0.025mmol), reaction is at room temperature stirred and is spent the night to add tetrakis triphenylphosphine palladium (0) then.Collect white precipitate by filtering,, obtain the alkylbenzyldimethylasaltsum saltsum (52mg) of title compound with tetrahydrofuran (THF) and ether washing.It is handled with 2N HCl and methyl alcohol, and solvent evaporation is dissolved among the DMSO/MeOH then again to doing, and by preparation property HPLC purifying, uses the 10-40% gradient elution, obtains title compound (22mg, 34.6%).NMR?δ H(400MHz，d 4-MeOD)0.00-0.05(m，2H)，0.37-0.43(m，2H)，0.67-0.77(m，1H)，1.61(q，2H，J＝7Hz)，4.06-4.11(m，2H)；m/z?255[MH +]。
Embodiment 10: 3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400352
A) 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400353
To 3-butyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (3.34g, (1.97g 14.8mmol), stirred 22 hours under room temperature and nitrogen atmosphere the 6-diketone then to add NCS in dry DMF 13.4mmol) (19ml) solution.The mixture vacuum concentration obtains yellow solid, uses methanol wash after the filtration.Filtrate concentrates the back and repeats above-mentioned steps.After the last washing of filtrate, (Si, 20g) column purification is with 1: 1 EtOAc: the hexanaphthene wash-out by SPE.After the solid vacuum-drying that merges, obtain title compound (2.42g, 64%); M/z 283.3[MH +].
B) 3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400361
With 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (100mg, 0.35mmol) Pd (PPh of the solution in anhydrous THF (4ml) and anhydrous DMSO (0.4ml) 3) 4(61mg 0.053mmol) handles.Mixture degasification under slight vacuum, (308 μ L 3.5mmol), stirred 4 hours under room temperature and nitrogen atmosphere to add morpholine.Yellow solution distributes between 2M HCl (aq) and EtOAc.Organic layer is used the salt water washing after separating, dry (MgSO 4) and concentrate.Resistates is dissolved among (taken up) MeOH, by aminopropyl SPE (5g), uses the MeOH wash-out, uses the 5%AcOH/MeOH wash-out again.The each several part product merges final vacuum and concentrates, and obtains the title compound (30mg, 35%) into pale solid.NMR；δ H(400MHz，d 6-DMSO)0.89(t，3H，J＝7.5Hz)，1.23-1.34(m，2H)，1.55-1.65(m，2H)，3.85(t，2H，J＝7Hz)，11.17(s，1H)，14.37(br.s，1H)；m/z?243.3[MH +]。
Embodiment 11: 8-chloro-3-propyl group-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400362
With 3-propyl group-3,7-dihydro-1H-purine-2, the 6-diketone (J.Med.Chem, 1993,36 (10), 1380-6) (0.3g, 1.5mmol) and N-chlorosuccinimide (0.21g 1.5mmol) is dissolved among the DMF (5ml) solution stirring 5 hours.After the solution concentration, the solid residue methanol wash is filtered the product (0.148g, 42%) that obtains to white solid.NMR; δ H(400MHz, d 6-DMSO) 0.85 (J=7Hz), 1.65 (m, 2H), 3.8 (J=7Hz), 11.2 (s, 1H), an exchangeable protons is not observed δ for t, 2H for t, 3H H13; M/z 229[MH +].
Embodiment 12: 8-chloro-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400371
A) 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400372
To 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (100mg, add in dry DMF 0.44mmol) (3ml) solution yellow soda ash (0.051g, 0.484mmol).After at room temperature stirring 10 minutes, (0.063ml 0.484mmol), continues to stir 18 hours under nitrogen atmosphere, room temperature to add the amyl group iodide.Reaction mixture water (25ml) dilution is with EtOAc (2x25ml) extraction.Dry organic extract (the MgSO that merges 4), filter and evaporation.(with 4: 1EtOAc/ hexanaphthene wash-out obtains the title compound (96mg, 74%) into white solid for Si, 5g) purifying by SPE; M/z 297.2[MH +].
B) 8-chloro-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400373
To contain tetrakis triphenylphosphine palladium (0) (56mg, 0.049mmol) the flask nitrogen wash, add 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3 then, 7-dihydro-1H-purine-2,6-diketone (96mg, 0.323mmol) anhydrous THF (1.5ml) solution, then add DMSO (0.1ml) and morpholine (0.28ml, 0.049mmol).Resulting mixture stirred 72 hours under room temperature, nitrogen atmosphere.Reaction mixture is dissolved among the EtOAc (25ml), with the 2M HCl aqueous solution (25ml) washing.Dry organic extract (MgSO 4), filter and reduction vaporization.By filling aminopropyl SPE (2g) purifying, use methanol wash, product is with the methanol solution wash-out of 5% acetate then.After containing the part evaporation of product, obtain title compound (27mg, 33%) into white solid.NMR；δ H(400MHz，d 6-DMSO)0.85(t，3H，J＝7Hz)，1.20-1.34(m，4H)，1.57-1.67(m，2H)，3.84(t，2H，J＝7Hz)，11.19(s，1H)，14.38(br.s，1H)；m/z?257.2[MH +]。
Embodiment 13: 8-chloro-3-(3-methyl butyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400381
A) 8-chloro-3-(3-methyl butyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400382
With 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (1.5g, (0.9g, 8.5mmol) (1.04g 6.9mmol) handles DMF 6.6mmol) (40ml) solution the 6-diketone with 1-bromo-3-methylbutane with yellow soda ash.Mixture after being mixed is 50 ℃ of down heating 18 hours, cools off then and is evaporated to dried.Resistates water (60ml) is handled, with ethyl acetate (3x80ml) extraction.Organic moiety is used dried over mgso after merging, and filters and evaporation.Resistates grinds with the mixture of diethyl ether and hexanaphthene, obtains the product into white solid, and it is leached after drying.Obtain title compound m/z 297[MH for white solid +].
B) 8-chloro-3-(3-methyl butyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400391
With 8-chloro-3-(3-methyl butyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (0.074g, THF 0.25mmol) (2ml) solution morpholine (0.035ml, 4.0mmol) handle, mixture is by applying vacuum repeatedly and nitrogen comes degasification in reactor.Mixture is used tetrakis triphenylphosphine palladium (0) (0.03g, 0.026mmol) solution-treated in the THF of degasification (0.5ml) subsequently.After 2 hours, mixture is handled with 2M aqueous hydrochloric acid (2ml) and diethyl ether (3ml).Leach the product that precipitation is separated out, with diethyl ether washing and dry.Obtain title compound (0.036g, 56%) for white solid.NMR?δ H(400MHz，d 6-DMSO)；0.91(d，6H，J＝6.3Hz)，1.47-1.62(m，3H)，3.87(t，2H，J＝7.5Hz)，11.19(br.s，1H)，14.38(br.s，1H)；m/z?257，259[MH +]。
Embodiment 14: 4-(8-chloro-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl) butyronitrile
Figure A20081009925400392
Use 4-bromine butyronitrile as alkylating reagent, according to embodiment 13 preparations.
NMR?δ H(400MHz，d 6-DMSO)；1.89-2.00(m，2H)，2.55(t，2H，J＝7.0Hz)，3.95(t，2H，J＝6.5Hz)，11.25(br.s，1H)，14.40(br.s，1H)；m/z?254[MH +]。
Embodiment 15: 8-chloro-3-(2-cyclohexyl ethyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400393
With 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (100mg, 0.442mmol) (52mg 0.486mmol) stirred 30 minutes in dry DMF (3ml) the 6-diketone with yellow soda ash.(93mg, 0.486mmol), mixture stirred 65 hours under 37-40 ℃, nitrogen atmosphere, then 90 ℃ of heating 18 hours down to add cyclohexyl ethyl bromide.After the cooling, solution is by finding time and introduce nitrogen for several times and degasification, add tetrakis triphenylphosphine palladium (0) (76mg, 0.066mmol) and morpholine (0.385ml, 4.42mmol), the mixture stirring is 18 hours then.(50mg 0.043mmol) and behind the morpholine (0.2ml), continues stirring 1 hour continue to add a certain amount of tetrakis triphenylphosphine palladium (0).Add the ethyl acetate and the 2M HCl aqueous solution (respectively being about 10ml), after organic layer separates, with salt water washing and evaporation.Resistates is dissolved among the THF, is seated on the 5g aminopropyl SPE post.Post washs with THF, and again with MeOH washing, acid product is with MeOH solution (rising to 10% by the 5%) wash-out of AcOH.Resulting product further by (autoprep) HPLC of preparation property automatically purifying, obtains title compound, 5.5mg, 3%.
NMR δ H(400MHz, d 6-DMSO) 0.80-0.95 (m, 2H), 1.05-1.35 (m, 4H), (m, 2H), (m, 3H), (m, 2H), 3.86 (J=8Hz), 11.07 (s, 1H), 1.70-1.80 does not observe 1.55-1.70 1.45-1.55 for t, 2H by an exchangeable protons.m/z?297(MH +)。
Embodiment 16: 3-butyl-1-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile
Figure A20081009925400401
A) 3-butyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400402
With the 7-(2-propylene-1-yl)-3 after stirring, 7-dihydro-1H-purine-2,6-diketone (10g, dry DMF 52mmol) (100ml) solution K 2CO 3(7.91g 57.2mmol) handles, add after 10 minutes BuI (6.51ml, 57.2mmol).React after 2 days, reaction mixture distributes between 2M HCl (aq) and EtOAc.Organic layer is used the salt water washing after separating, dry (MgSO 4) and vacuum concentration, obtain pale solid.It with hot hexanaphthene washing and vacuum-drying, is obtained title compound (8.87g, 68%); M/z249.3[MH +].
B) 3-butyl-1-methyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400411
With the 3-butyl-7-(2-propylene-1-yl)-3 after stirring, 7-dihydro-1H-purine-2,6-diketone (1.0g, dry DMF 4.03mmol) (10ml) solution Na 2CO 3(470mg 4.43mmol) handles, and (275 μ l 4.43mmol) handle to use the methyl iodide again.Mixture heated 17 hours down at 35 ℃.Add K 2CO 3(500mg, 3.6mmol) (275 μ l 4.43mmol), continue down to stir 18 hours at 50 ℃ then with the methyl iodide.Reaction mixture put cold after, between 2M HCl (aq) and EtOAc, distribute.After organic layer separated, water layer with the EtOAc extraction more than once.The extract salt water washing that merges, dry (MgSO 4) and the concentrated yellow/brown oily matter (1.24g) that obtains.Product is by silicon-dioxide SPE (10g) purifying, with EtOAc/ hexanaphthene mixture wash-out.After product partly merges, concentrate the title compound (1.11g, quantitative) that obtains to light yellow solid; M/z 263.3[MH +].
C) 3-butyl-1-methyl-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-8-formaldehyde
Figure A20081009925400412
To be filled with 3-butyl-1-methyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (300mg, 1.14mmol) the predrying flask with anhydrous THF (6ml) is cooled to-75 ℃ to the 6-diketone under nitrogen atmosphere, uses LiHMDS (the 1.0M THF solution of 1.37ml) to handle then.Resulting solution was warmed to-60 ℃ in 1.5 hours, add then dry DMF (177 μ l, 2.29mmol).Solution was warmed to-10 ℃ in 3 hours, then it is used saturated NH 4The quencher of Cl (aq) solution.Mixture distributes between 1M HCl (aq) and EtOAc.Organic layer is used the salt water washing after separating, dry (MgSO 4) and the concentrated brown oil (350mg) that obtains.(Si, 10g) purifying with EtOAc/ hexanaphthene mixture wash-out, obtain the title compound (131mg, 39%) into white solid to product by SPE; NMR; δ H(400MHz, d 6-DMSO) 0.91 (t, 3H, J=7.5Hz), 1.28-1.39 (m, 2H), 1.63-1.73 (m, 2H), 3.25 (s, 3H), 4.02 (t, 2H, J=7.5Hz), 5.03 (dd, 1H, J=17 and 1Hz), 5.17 (dd, 1H, J=10 and 1Hz), 5.31 (app.d, 2H, J=5.5Hz), 5.98-6.09 (m, 1H), 9.88 (s, 1H).
D) 3-butyl-1-methyl-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile
With 3-butyl-1-methyl-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6, (63mg 0.91mmol) handles anhydrous pyridine (5ml) solution of 7-tetrahydrochysene-1H-purine-8-formaldehyde, heats 1 hour down at 50 ℃ simultaneously with hydroxylamine hydrochloride.Mixture put cold after, concentrate, handle with diacetyl oxide (5ml), then 100 ℃ of heating 2.5 hours down, 125 ℃ of heating 45 minutes down.Mixture put once more cold after, between water and EtOAc, distribute.Organic layer is used the salt water washing after separating, dry (MgSO 4) and concentrate, obtain title compound (230mg crude product, 114%) into yellow residue; M/z 288.3[MH +].
E) 3-butyl-1-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile
Figure A20081009925400422
With 3-butyl-1-methyl-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile (230mg, 0.80mmol) Pd (PPh of the solution in anhydrous THF (5ml) and anhydrous DMSO (0.5ml) 3) 4(185mg 0.16mmol) handles.Mixture degasification under slight vacuum adds morpholine (698 μ L), places under room temperature, nitrogen atmosphere and stirs 2 hours.Yellow solution distributes between 2M HCl (aq) and EtOAc.Organic layer is used the salt water washing after separating, dry (MgSO 4) and concentrate.Resistates is dissolved among the MeOH, by aminopropyl SPE (5g), uses MeOH, 5%AcOH, 10%, 20% and 30%AcOH/MeOH mixture wash-out successively.Product partly merges the concentrated light yellow solid (116mg) that obtains in back.It is washed with MeOH, for the title compound of white solid is collected vacuum-drying then (55mg, 28%) by filtering.NMR; δ H(400MHz, d 6-DMSO) 0.90 (J=7.5Hz), (m, 2H), (m, 2H), 3.24 (s, 3H), 3.96 (J=7Hz), NH does not observe δ to 1.59-1.68 to 1.25-1.35 for t, 2H for t, 3H H15; M/z 248.2[MH +].
Embodiment 17: 1-methyl-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile
Figure A20081009925400431
A) 3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400432
With 7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (0.61g, 3.2mmol), yellow soda ash (0.60g, 5.7mmol) and the amyl group iodide (0.64g, 3.2mmol) among 50 ℃ DMF (5ml) the stirring 18 hours.After the solution cooling, distribute between ethyl acetate and salt solution, organic layer separates after drying (MgSO 4) and concentrate.Chromatography on silicon-dioxide is (with methylene dichloride to 5: 1 dichloromethane/ethyl acetate gradient elution), obtain the title compound (0.47g, 56%) into light yellow solid.m/z?263[MH +]。
B) 1-methyl-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400433
With 3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (0.20g, 0.76mmol), salt of wormwood (0.4g, 2.9mmol) and methyl iodide (0.5ml, 4.9mmol) stirring heating 3 hours in 50 ℃ DMF (5ml).Solution is put cold back and is distributed between ethyl acetate and salt solution.After organic layer separates, dry (MgSO 4) and concentrate, obtain title compound (0.21g, 100%).m/z?277[MH +]。
C) 1-methyl-2,6-dioxo-3-amyl group-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-8-formaldehyde
Figure A20081009925400441
Under-78 ℃, to 1-methyl-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (1.05g added LiHMDS (4ml, 1M hexane solution to the 6-diketone in 10 minutes in THF 3.6mmol) (15ml) solution, 4mmol), solution stirring is 0.5 hour.Add DMF (0.5ml), solution continues to stir 0.5 hour down at-78 ℃, is warmed to envrionment temperature with cooling bath in 2 hours then.Reaction distributes between ethyl acetate and salt solution then with 2N hydrochloric acid (3ml) quencher.Organic layer separates after drying and concentrates.Crude product on silicon-dioxide chromatography (with methylene dichloride to 5: 1 dichloromethane/ethyl acetate gradient elution), obtain title compound (0.35g, 30%) into white solid.m/z?305[MH +]。
D) 1-methyl-2,6-dioxo-3-amyl group-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile
Figure A20081009925400442
With 1-methyl-2,6-dioxo-3-amyl group-7-(2-propylene-1-yl)-2,3,6, and 7-tetrahydrochysene-1H-purine-8-formaldehyde (0.18g, 0.6mmol) and hydroxylamine hydrochloride (0.053g, 0.76mmol) in 50 ℃ pyridines (5ml), heated 1 hour, be cooled to envrionment temperature then.Add diacetyl oxide (0.08g, 0.78mmol) after, solution stirring 18 hours.Solution concentration obtains acetic ester, and it is dissolved in the diacetyl oxide (3ml), is heated to 130 ℃ simultaneously, continues 3 hours, and the cooling back concentrates and obtains crude product.Chromatography on silicon-dioxide (using the methylene dichloride wash-out) obtains the title compound (0.17g, 95%) into transparent oily matter.m/z?302[MH +]。
E) 1-methyl-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile
Figure A20081009925400451
With 1-methyl-2,6-dioxo-3-amyl group-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile (0.17g, 0.56mmol) and morpholine (0.6ml 6.7mmol) is dissolved among the THF (5ml) that contains DMSO (0.5ml).The flask that will contain this solution places under the vacuum, with nitrogen replacement air (x3) wherein.Adding tetrakis triphenylphosphine palladium (0) (0.13g, 0.11mmol), solution stirring 2.5 hours.Solution distributes between ethyl acetate (20ml) and 2N hydrochloric acid (10ml), after organic layer separates, with salt solution (3x10ml) washing.Organic layer washs with 2N sodium hydroxide solution (2x10ml) then, and water layer 2N hcl acidifying is with ethyl acetate (2x10ml) extraction.After organic layer separates, dry (MgSO 4) and the concentrated title compound (0.026g, 18%) that obtains.NMR；δ H(400MHz，CDCl 3)0.92(t，3H，J＝7Hz)，1.32-1.43(m，4H)，1.79(m，2H)，3.54(s，3H)，4.15(t，2H，J＝7.5Hz)，14.35(b?r.s，1H)；m/z?262[MH +]。
Embodiment 18: 8-chloro-3-hexyl-1-methyl-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400452
A) 8-chloro-3-({ [2-(methoxyl group) ethyl] oxygen base } methyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400453
To 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (6g, add in dry DMF 26.5mmol) (30ml) solution yellow soda ash (3.09g, 29.15mmol).After at room temperature stirring 10 minutes, (3.03ml 26.5mmol), continues to stir 66 hours under nitrogen atmosphere and room temperature to add the methoxyethoxy Methochloride.Behind the reaction mixture vacuum concentration, resistates is dissolved among the EtOAc (100ml), and with salt solution (100ml) washing, aqueous extract extracts with DCM (100ml), dry organic extract (MgSO 4) and merge final vacuum and concentrate.Resistates grinds with EtOAc, leaches solid.Filtrate concentrates and to obtain light brown oily matter, and it is adsorbed on the silicon-dioxide, and (Si, 50g) purifying are EtOAc/ hexanaphthene-EtOAc wash-out of 1: 1 with gradient, obtain the title compound (2g, 24%) into white solid, m/z315.2[MH by SPE +].
B) 8-chloro-1-methyl-3-({ [2-(methoxyl group) ethyl] oxygen base } methyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400461
To 8-chloro-3-({ [2-(methoxyl group) ethyl] oxygen base } methyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (2g, add in dry DMF 6.37mmol) (15ml) solution yellow soda ash (0.743g, 7mmol).After at room temperature stirring 10 minutes, (0.44ml 7mmol), continues to stir 18 hours under nitrogen atmosphere and room temperature to add the methyl iodide.Behind the reaction mixture vacuum concentration, resistates is dissolved among the EtOAc (100ml), with salt solution (100ml) washing.Dry organic extract (MgSO 4), filter and evaporation obtain into brown oily matter title compound (85% purity) (2.98g, quantitatively), m/z 329.2[MH +].
C) 8-chloro-1-methyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400462
To 8-chloro-1-methyl-3-({ [2-(methoxyl group) ethyl] oxygen base } methyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (2.9g 6.37mmol) adds 5M HCl (20ml) to the 6-diketone in De diox (20ml) and water (20ml) solution.The heating 18 hours under 100 ℃ and nitrogen atmosphere of resulting mixture.Reaction mixture is vacuum concentration subsequently, and resistates is dissolved among the EtOAc (100ml), washes with water.Dry organic extract (MgSO 4), filter and evaporation.(Si, 20g) purifying with 2: 3 EtOAc/ hexanaphthene wash-outs, obtain the title compound (1.04g, 68%) into white solid by SPE.m/z?241.1[MH +]。
Perhaps, 8-chloro-1-methyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone also can adopt the SEM protection to prepare.
A) 8-chloro-7-(2-propylene-1-yl)-3-({ [2-(trimethyl silyl) ethyl] oxygen base } methyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400471
To 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (5g adds 2-2-(trimethyl silyl) ethoxymethyl chloride (4.3ml to the 6-diketone in DMF 22.1mmol) (80ml) solution, 24.2mmol) and yellow soda ash (2.6g, 24.2mmol).At room temperature stir spend the night after, continue to add 2-2-(trimethyl silyl) ethoxymethyl chloride (4.3ml, 24.2mmol) and yellow soda ash (1.3g 12.1mmol), continues stirring 2 hours.Reaction mixture distributes between the 5%LiCl aqueous solution and ethyl acetate subsequently.Organic extract is used the salt water washing after separating, dry (MgSO 4) and concentrate.By using the Biotage of silica column TMChromatography purification, with 1: 4-1: 2 ethyl acetate/hexanaphthene wash-out obtain title compound (3.14g, 40%); M/z 374.2[MNH 4 +].
B) 8-chloro-1-methyl-7-(2-propylene-1-yl)-3-({ [2-(trimethyl silyl) ethyl] oxygen base } methyl)-3,7-dihydro-1H-purine-2,6-diketone
To 8-chloro-7-(2-propylene-1-yl)-3-({ [2-(trimethyl silyl) ethyl] oxygen base } methyl)-3,7-dihydro-1H-purine-2,6-diketone (3.14g, 8.82mmol) DMF (50ml) solution in add methyl iodide (0.659ml, 10.58mmol) and cesium carbonate (3.45g, 10.58mmol), reaction mixture at room temperature stirs and spends the night.Reaction mixture distributes between water and ethyl acetate.Organic extract is used the salt water washing after separating, dry (MgSO 4) and concentrate, obtain title compound 2.99g (92%); M/z 388[MNH 4 +].
C) 8-chloro-1-methyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400481
To 8-chloro-1-methyl-7-(2-propylene-1-yl)-3-({ [2-(trimethyl silyl) ethyl] oxygen base } methyl)-3,7-dihydro-1H-purine-2, (2.99g adds TFA (10ml) in DCM 8.08mmol) (20ml) solution to the 6-diketone, and reaction was at room temperature stirred 2.5 hours.Reaction mixture concentrates subsequently, and resistates is handled with DCM again, and evaporation simultaneously more than once.By SPE (Si) purifying, with 1: 9-4: 1 ethyl acetate/hexanaphthene wash-out, obtain not pure products (1.31g), it is dissolved in the methyl alcohol (20ml), handle with unsaturated carbonate aqueous solutions of potassium (20ml).After stirring was spent the night, mixture distributed between water that contains 2M HCl (1ml) and ethyl acetate.Organic extract is used the salt water washing after separating, dry (MgSO 4) and the concentrated title compound 0.87g (45%) that obtains; M/z 241.1[MH +].
D) 8-chloro-3-hexyl-1-methyl-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400482
To 8-chloro-1-methyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (100mg, 0.42mmol) dry DMF (3ml) solution in add yellow soda ash (58mg, 0.54mmol), stir after 10 minutes, add hexyl iodide (0.08ml, 0.54mmol), reaction mixture stirred 90 hours under room temperature and nitrogen atmosphere.Add Pd (PPh then 3) 4(73mg, 0.063mmol), with nitrogen wash (x3), (0.37ml 4.3mmol), continued to stir 4 hours under room temperature and nitrogen atmosphere to add morpholine after reactor was found time.Reaction mixture is with EtOAc (25ml) dilution, with the 2M HCl aqueous solution (25ml) washing.Dry organic extract (MgSO 4), filter and evaporation.By compound being packed into aminopropyl SPE (5g) purifying, after the MeOH washing, product 5%AcOH/MeOH wash-out obtains the title compound (65mg, 54%) into white solid.NMR；δ H(400MHz，d 6-DMSO)0.85(t，3H，J＝7Hz)，1.23-1.33(m，6H)，1.58-1.68(m，2H)，3.22(s，3H)，3.91(t，2H，J＝7.5Hz)，14.46(br.s，1H)；m/z?285.3[MH +]。
Embodiment 19: 8-chloro-1-methyl-3-propyl group-3,7-dihydro-1H-purine-2,6-diketone
Prepare according to the mode that is similar to embodiment 18, but be to use the alkylation on N3 of propyl iodide thing.NMR?δ H(400MHz，d 6-DMSO)0.87(t，3H，J＝7.5Hz)，1.61-1.73(m，2H)，3.22(s，3H)，3.89(t，2H，J＝7.5Hz)，14.45(br.s，1H)，m/z?243[MH +]。
Embodiment 20: 1,3-dibutyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile
Figure A20081009925400492
A) 1,3-dibutyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400493
With 1,3-two-N-butyl xanthine (10g, dry DMF 38mmol) (80ml) solution K 2CO 3(5.2g 38mmol) handles, and (3.6ml 42mmol) handles the olefinic recycle propyl bromide.Mixture heating 18 hours under 55 ℃ and nitrogen atmosphere.After being cooled to room temperature, mixture distributes between water and EtOAc.Adding several milliliters of 2M HCl (aq) helps to separate.After organic layer separated, water layer with the EtOAc extraction more than once.The extract salt water washing that merges, dry (MgSO 4) and concentrate, obtain title compound (12.23g, 106%) into pale solid.m/z?305.3[MH +]。
B) 1,3-dibutyl-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-8-carboxylate methyl ester
Figure A20081009925400501
With 1,3-dibutyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (3.0g, anhydrous THF (30ml) solution 9.9mmol) is cooled to-50 ℃ to the 6-diketone, and (the 1.0M THF solution of 18ml 17.8mmol) is handled with LiHMDS.At-50 ℃ after following 1 hour, (1.9ml, 24.6mmol), mixture was warmed to-30 ℃ in 2 hours, use saturated NH then to add methyl-chloroformate 4The quencher of Cl (aq) solution.Mixture distributes between EtOAc and 1M HCl (aq).Organic layer is used the salt water washing after separating, dry (MgSO 4) and concentrate, obtain dark orange (4.07g).This oily matter is dissolved in (taken up) 15%EtOAc/ hexanaphthene, by Si Biotage TMChromatographic column.After product partly merges, concentrate the title compound (1.35g, 38%) that obtains to yellow solid.m/z?363.2[MH +]。
C) 1,3-dibutyl-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-8-carboxylic acid
Figure A20081009925400502
With 1 after stirring, 3-dibutyl-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-8-carboxylate methyl ester (1.30g, handle with LiOH (215mg) and water (1.5ml) by MeOH 3.6mmol) (15ml) solution.After at room temperature handling 3 hours, the mixture dilute with water is regulated pH to about pH 5 with 2M HCl (aq).Separate after adding EtOAc, use the salt water washing, dry (MgSO 4) and concentrate, obtain title compound 85% purity (1.2g, 88%) into yellow solid.m/z.349.2[MH +]。
D) 1,3-dibutyl-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-8-methane amide
Figure A20081009925400511
With 1 after stirring, 3-dibutyl-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6, (1.0g, dry DMF 2.9mmol) (10ml) solution is used DIPEA (1.1ml), PyBOP and 2M NH to 7-tetrahydrochysene-1H-purine-8-carboxylic acid successively 3(3.6ml) handle.After 2 hours, product mixtures is distributed between 2M HCl (aq) and EtOAc.Organic layer is used saturated NaHCO after separating 3(aq) solution, salt water washing, dry (MgSO 4) and concentrate, obtain orange (approximately 2g).Product passes through Biotage TMChromatography purification is with 5% → 40%EtOAc/ hexanaphthene mixture wash-out.Suitable part merges concentrated acid amides 90% purity (790mg, 78%) that obtains in back.M/z.392.3[M+ formic acid-H] -
E) 1,3-dibutyl-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile (carbonitrile)
Figure A20081009925400512
With 1,3-dibutyl-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6, dry DMF (7ml) solution of 7-tetrahydrochysene-1H-purine-8-methane amide (300mg) is dropwise used POCl under 0 ℃ 3(237 μ L) handles.Remove ice bath, mixture is at water and Et after 2 hours 2Distribute between the O.Water layer is used Et once more 2The O extraction, after the extract of merging separates, water (x2), salt water washing, dry then (MgSO 4) and concentrate, obtain yellow oil (312mg).This oily matter is dissolved in (taken up) hexanaphthene, (Si, 10g) purifying is with EtOAc/ hexanaphthene mixture wash-out by SPE.After the product partial concentration, obtain title compound (150mg, 53%) into colorless oil; M/z.330.3[MH +].
F) 1,3-dibutyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile
Figure A20081009925400521
With 1,3-dibutyl-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-8-nitrile (140mg, 0.43mmol) Pd (PPh of the solution in anhydrous THF (4ml) and anhydrous DMSO (0.4ml) 3) 4(74mg 0.064mmol) handles.Mixture degasification under slight vacuum adds morpholine (371 μ L).Under room temperature and nitrogen atmosphere, place and stirred 4 hours.Yellow solution distributes between 2M HCl (aq) and EtOAc.Organic layer is used the salt water washing after separating, dry (MgSO 4) and concentrate.Resistates is dissolved among (taken up) MeOH,, uses MeOH, 5% → 50%AcOH/MeOH wash-out successively by aminopropyl SPE (5g).The product of wash-out contains a little impurity after concentrating, and obtains the title compound (30mg, 24%) into pale solid after cleaning with hexanaphthene.NMR δ H(400MHz, d 6-DMSO) 0.89 (app.td, 6H, J=7 and 3Hz), (m, 4H), (m, 2H), (m, 2H), 3.87 (J=7Hz), 3.95 (J=7Hz), NH does not observe δ to 1.58-1.69 to 12.48-1.55 to 1.25-1.35 for t, 2H for t, 2H H15; M/z 290.3[MH +].
Embodiment 21: 1,3-dibutyl-8-iodo-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400522
With 1 after stirring, (100mg, (94mg 3.75mmol) handles dry DMF 3.39mmol) (3ml) solution 3-two-N-butyl xanthine, places under room temperature and nitrogen atmosphere then and stirs 23 hours with NIS.Mixture is at saturated Na 2SO 3(aq) distribute between solution and the EtOAc.Organic layer is used the salt water washing after separating, dry (MgSO 4) and vacuum concentration.Product is through (Si, 5g) column purification is with EtOAc/ hexanaphthene mixture wash-out by SPE.The product partial concentration obtains the title compound (75mg, 51%) into white solid; NMR; δ H(400MHz, d 6-DMSO) (app.td, 6H, J=7.5 and 4Hz), 1.21-1.34 (m, 4H), 1.45-1.54 (m, 2H), 1.56-1.66 (m, 2H), 3.84 (t, 2H, J=7.5Hz), 3.93 (t, 2H, J=7.5Hz), 14.10 (s, 1H); M/z 391.3[MH +].
Embodiment 22: (3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) acetonitrile
To 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (200mg, 0.707mmol) and Cs 2CO 3(254mg, add in dry DMF 0.778mmol) (5ml) solution chloromethyl cyanide (0.054ml, 0.85mmol).Mixture heated 18 hours down at 50 ℃, was cooled to room temperature then, and nitrogen is introduced in degasification under slight vacuum subsequently.Repeat twice of above-mentioned steps.Add Pd (PPh 3) 4(82mg, 0.071mmol), the mixture degasification more than once, (0.617ml, 7.07mmol), mixture is at room temperature placed and was stirred 3 hours to add morpholine then.Mixture distributes between 2M HCl (aq) and EtOAc.Organic layer is used the salt water washing after separating, dry (MgSO 4) and concentrate.Resistates is dissolved among (takenup) MeOH,, uses the MeOH wash-out, use the 5-10%AcOH/MeOH wash-out again by aminopropyl SPE (5g).The product partial concentration obtains title compound 52mg (26%); NMR; δ H(400MHz, d 6-DMSO) 0.90 (t, 3H, J=7.5Hz), 1.26-1.37 (m, 2H), 1.60-1.69 (m, 2H), 3.94 (t, 2H, J=7.5Hz), 4.87 (s, 2H), 14.72 (br s, 1H); M/z 299.2[MNH 4 +].
Embodiment 23: (8-chloro-2,6-dioxo-3-propyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) acetonitrile
Figure A20081009925400532
A) 8-chloro-7-(2-propylene-1-yl)-3-propyl group-3,7-dihydro-1H-purine-2,6-diketone
With 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (1.5g, 6.6mmol), propyl iodide (1.2g, 6.9mmol) and yellow soda ash (0.9g, 8.5mmol) mixture in DMF (40ml) is 50 ℃ of down heating 18 hours.Behind the reaction mixture vacuum concentration, resistates water (60ml) is handled, with ethyl acetate (3x80ml) extraction.Dry organic extract (the MgSO that merges 4), filter and evaporation.Resistates grinds with ether/hexanaphthene, and solid leaches after drying and obtains title compound (0.82g, 46%); M/z269.1[MH +].
B) (8-chloro-2,6-dioxo-3-propyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) acetonitrile
Figure A20081009925400542
With 8-chloro-7-(2-propylene-1-yl)-3-propyl group-3,7-dihydro-1H-purine-2, (0.067g, (0.082g, 0.25mmol) (0.044g 0.37mmol) handles DMF 0.25mmol) (2ml) solution the 6-diketone with the bromo acetonitrile with cesium carbonate.Mixture heated 4 hours down at 80 ℃, was cooled to envrionment temperature then.Vacuum is removed DMF, and resistates is handled with THF (2ml).Solvent is by applying vacuum and nitrogen comes degasification to reaction mixture continuously.Mixture use subsequently morpholine (0.035ml, 0.4mmol) and tetrakis triphenylphosphine palladium (0) (0.03g 0.026mmol) handles.After 2 hours, mixture is handled with 2M aqueous hydrochloric acid (2ml), and product extracts with chloroform (3x5ml).Organic moiety merges the back evaporation.Resistates obtains the title compound (0.022g, 33%) into white solid by the directed HPLC purifying of quality.NMR; δ H(400MHz, d 6-DMSO), 0.88 (J=7.5Hz), (m, 2H), 3.91 (J=7.5Hz), 4.87 (s, 2H), NH does not observe δ to 1.63-1.74 for t, 2H for t, 3H H14; M/z 268[MH +].
Embodiment 24: [8-chloro-3-(2-cyclopropyl ethyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1- Base] acetonitrile
Figure A20081009925400551
Use 8-chloro-3-(2-cyclopropyl ethyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone prepares according to (8-chloro-2,6-dioxo-3-propyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) acetonitrile (embodiment 23).
NMR?δ H(400MHz，d 6-DMSO)-0.06-0.00(m，2H)，0.31-0.39(m，2H)，0.64-0.74(m，1H)，1.57(q，2H，J＝7Hz)，4.04(t，2H，J＝7Hz)，4.87(s，2H)，14.68(br.s，1H)；m/z?294[MH +]。
Embodiment 25: 8-chloro-1-ethyl-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400552
A) 8-chloro-7-(2-propylene-1-yl)-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400553
To 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (1.5g, 6.62mmol) dry DMF (50ml) solution in add sodium bicarbonate (0.98g 9.25mmol), add 1 again, 1,1-three fluoro-2-iodoethane (1.20g, 5.72mmol), mixture stirring heating 6 hours under 50 ℃ and nitrogen atmosphere.Solution, heated 48 hours down at 120 ℃ to envrionment temperature then at 10 hours internal cooling.Add in addition 1,1, (0.43g, 2.05mmol), mixture heating up to 120 ℃ continues to continue 3 hours 1-three fluoro-2-iodoethane.After the removal of solvent under reduced pressure, resistates grinds with DCM, filters then.
Use 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (3.80g, 16.8mmol), sodium bicarbonate (2.45g, 23.1mmol) and 1,1, (4.05g 19.3mmol) repeats above-mentioned reaction to 1-three fluoro-2-iodoethane in dry DMF (125ml).Mixture heated 16 hours down at 120 ℃, and after the removal of solvent under reduced pressure, resistates grinds with DCM, filtered then.
Merge preceding twice resulting DCM filtrate, behind the concentrating under reduced pressure, use Biotage TMChromatography purification (using cyclohexane/ethyl acetate 1: 1,7: 3 wash-outs successively) obtains the title compound (1.6g, 23%) into white solid.m/z?309[MH +]。
B) 8-chloro-1-ethyl-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400561
To 8-chloro-7-(2-propylene-1-yl)-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2, (0.070g adds cesium carbonate (0.085g in dry DMF 0.23mmol) (2ml) solution to the 6-diketone, 0.26mmol), add again the 1-iodoethane (0.061g, 0.39mmol).Mixture heated 5 hours down at 80 ℃, stirred 16 hours under envrionment temperature and nitrogen atmosphere then.Use the vacuum centrifuge removal of solvent under reduced pressure, resistates is dissolved among the anhydrous THF (2.5ml).In mixture, add tetrakis triphenylphosphine palladium (0) (0.030g, 0.026mmol) and morpholine (0.040g, 0.45mmol), reaction mixture nitrogen degasification was stirred 72 hours then at ambient temperature.Mixture distributes between the chloroform and the 2N HCl aqueous solution, and water layer extracts again.After organic extract merges, under nitrogen gas stream, evaporate, use aminopropyl SPE purifying (use acetate: methyl alcohol: DCM, 1: 2: 2 wash-out) then, obtain title compound＞95% purity (0.041g, 60%) into white solid.NMR?δ H(400MHz，d 4-MeOD)1.20(t，3H，J＝7Hz)，4.03(q，2H，J＝7Hz)，4.73(q，2H，J＝8.5Hz)，m/z?297[MH +]。
Embodiment 26: 8-chloro-1-propyl group-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-diketone
Use the alkylation on N1 of propyl group iodide, prepare according to the mode that is similar to embodiment 25.
NMR δ H(400MHz, CDCl 3) 0.99 (J=7.5Hz), (m, 2H), 4.07 (J=7.5Hz), 4.77 (J=8.5Hz), NH does not observe δ to 1.68-1.79 for q, 2H for t, 2H for t, 3H H13; M/z 311[MH +].
Embodiment 27: 8-chloro-1-(4,4,4-trifluoro butyl)-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine -2, the 6-diketone
Figure A20081009925400571
Use 4-bromo-1,1, the alkylation on N1 of 1-trifluoro butane prepares according to the mode that is similar to embodiment 25.
NMR；δ H(400MHz，d 4-MeOD)1.83-1.95(m，2H)，2.14-2.32(m，2H)，4.06(t，2H，J＝7Hz)，4.74(q，2H，J＝8.5Hz)，m/z?377[M-H] -。
Embodiment 28: 8-bromo-1-methyl-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400572
A) 1-methyl-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400573
With 1-methyl-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, and the 6-diketone (0.45g, 1.63mmol), phenyl silane (0.25ml, 2.03mmol) and tetrakis triphenylphosphine palladium (0) (0.35g 0.3mmol) is dissolved among the DCM (10ml) that contains acetate (6ml).By the flask of finding time, insert nitrogen (x3) then, go out air in the flask with nitrogen replacement, reaction mixture is heated to 45 ℃ then, continue 4 hours.After the solution cooling, with the DCM dilution, water and saturated sodium bicarbonate solution washing then.After organic layer separates, the dry and concentrated crude product that obtains.By SPE (silicon-dioxide) purifying, obtain product 0.06g, 16% with the ether wash-out.m/z?237[MH +]。
B) 8-bromo-1-methyl-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400581
With 1-methyl-3-amyl group-3,7-dihydro-1H-purine-2, the 6-diketone (0.06g 0.25mmol) is dissolved among the DMF (2ml), and the adding N-bromosuccinimide (0.045g, 0.25mmol).Mixture stirred after 18 hours, concentrated, and crude product is used 5% acetate/methanol-eluted fractions product with methyl alcohol earlier again by aminopropyl SPE (5g) wash-out purifying.Product further by directed automated preparation (the mass directed autoprep) purifying of quality, obtains the title compound (0.01g, 12%) into white solid.NMR?δ H(400MHz，d 6-DMSO)0.86(t，3H，J＝7Hz)，1.21-1.35(m，4H)，1.59-1.68(m，2H)，3.22(s，3H)，3.91(t，2H，J＝7.5Hz)，14.39(br.s，1H)；m/z?315，317[MH +]。
Embodiment 29: 8-chloro-1-methyl-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-1-methyl-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
To 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (3.9g, 13.3mmol) DMF (35ml) solution in add cesium carbonate, mixture stirred 10 minutes, added methyl iodide (0.91ml then, 14.6mmol), mixture stirred 18 hours.Be reflected between ethyl acetate and the 2N HCl solution and distribute, after organic layer separates, dry (MgSO 4) and concentrate.Chromatography on silicon-dioxide SPE with cyclohexane/ethyl acetate (5%-20%) wash-out, obtains the product 2.78g into oily matter, 68%.m/z?311[MH +]。
B) 8-chloro-1-methyl-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400591
With tetrakis triphenylphosphine palladium (1.0,0.90mmol) place the flask that is full of nitrogen (x3) after finding time again.Add 8-chloro-1-methyl-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (find time more than once, introduces nitrogen then for 2.78g, the 8.96mmol) solution in 50ml THF by flask.Adding DMSO (4.5ml) and morpholine (7.8ml, 89.6mmol), solution stirring 5 hours.Solution distributes between ethyl acetate and 2N HCl solution, organic moiety salt water washing, dry (MgSO 4) and concentrate.Crude product is used the methanol-eluted fractions that contains 0-15% acetate with methyl alcohol earlier again by aminopropyl SPE purifying, obtains the title compound 1.12g into white solid, 46%.NMR?δ H(400MHz，d 6-DMSO)0.86(t，3H，J＝7Hz)，1.21-1.35(m，4H)，1.59-1.68(m，2H)，3.22(s，3H)，3.91(t，2H，J＝7.5Hz)，NH?not?observed；m/z?271[MH +]。
Embodiment 30: 3-butyl-8-chloro-1-methyl-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400592
Use 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone prepare according to the mode that is similar to embodiment 29 as raw material.
NMR?δ H(400MHz，d 6-DMSO)0.88(t，3H，J＝7Hz)，1.25-1.35(m，2H)，1.6-1.66(m，2H)，3.22(s，3H)，3.91(t，2H，J＝7.5Hz)，14.46(br?s，1H)；m/z?257[MH +]。
Embodiment 31: 4-(8-chloro-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl) butyronitrile
To 8-chloro-1-methyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (70mg, 0.292mmol) and Na 2CO 3(37mg, 0.35mmol) add in the mixture in DMF (3ml) 4-bromine butyronitrile (0.035ml, 0.35mmol).Mixture at room temperature stirs and spends the night, degasification and introduce nitrogen under slight vacuum then.Add Pd (PPh then successively 3) 4(50mg, 0.044mmol) and morpholine (0.254ml, 2.92mmol).After at room temperature stirring 2 hours, further add the Pd (PPh of existing system 3) 4(50mg 0.044mmol), continues to stir and spends the night.Reaction mixture distributes between ethyl acetate (20ml) and water (20ml), adds a small amount of 2M HCl simultaneously to help separation.Organic layer is used the salt water washing after separating, dry (MgSO 4) and concentrate.Resistates is dissolved among (taken up) MeOH, by amino-propyl group SPE (5g), uses MeOH, 3-5%AcOH/MeOH wash-out successively.The product partial concentration obtains title compound 39.7mg (51%); NMR; δ H(400MHz, d 6-DMSO) 1.91-2.00 (m, 2H), 2.55 (t, 2H, J=7Hz), 3.22 (s, 3H), 4.03 (t, 2H, J=7Hz), 14.49 (br.s, 1H); M/z 268.1[MH +].
Embodiment 32: 8-chloro-1-methyl-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400602
With 8-chloro-1-methyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (0.048g, (0.78g, 0.24mmol) with 4-bromo-1,1, (0.044g 0.25mmol) handles 1-trifluoro butane THF 0.2mmol) (1ml) solution the 6-diketone with cesium carbonate.Mixture stirred 1 hour at ambient temperature, heated 4 hours down at 50 ℃ then, with postcooling.Mixture is by alternately applying vacuum and nitrogen pressure is come degasification to mixture, use morpholine (0.17ml then, 2mmol) and tetrakis triphenylphosphine palladium (0) (0.023g, 0.02mmol) handle, after 2 hours, mixture uses 2M aqueous hydrochloric acid (2ml) to handle carefully, and product extracts with chloroform (2x4ml).After the organic layer evaporation that merges, product obtains title compound 6.2mg (10%) by the directed HPLC purifying of anti-phase quality; NMR; δ H(400MHz, d 6-DMSO); 1.84-1.92 (m, 2H), 2.28-2.35 (m, 2H), 3.22 (s, 3H), 3.99-4.03 (m, and 2H) 14.31 (br.s, 1H); M/z 311.2[MH +].
Embodiment 33: 3-butyl-8-chloro-1-ethyl-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400611
A) 3-butyl-7-(phenyl methyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400612
Under 40 ℃, with 7-benzyl-3,7-dihydro-1H-purine-2, (17.14g, 70.8mmol) (11.43g 82.8mmol) is suspended among the DMF (400ml) the 6-diketone for [Synthetic Communications, 20 (16), 2459-2467,1990] and salt of wormwood.Stir after 30 minutes, (8.76mL, 77.0mmol), mixture stirs down at 40 ℃ and spends the night to add the butyl iodide.Add 50% acetic acid aqueous solution (60ml), solution decompression concentrates.Resistates is suspended in the water (500ml), the product chloroform extraction.Organic layer merges the back and concentrates, and product is separated with flash chromatography, with the dichloromethane solution wash-out of 1% methyl alcohol, obtains product (9.49g, 45%); 1H NMR (400MHz; CDCl 3) δ: 0.95 (3H, t), 1.34-1.41 (2H, m), 1.70-1.78 (2H, m), 4.05 (2H, t), 5.46 (2H, s), 7.31-7.40 (5H, m), 7.56 (1H, s), 8.21 (1H, br.s); M/z 299[MH +].
B) 3-butyl-1-ethyl-7-(phenyl methyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400613
With 3-butyl-7-(phenyl methyl)-3,7-dihydro-1H-purine-2, the 6-diketone (0.429g, 1.24mmol) and salt of wormwood (0.256g 1.85mmol) is suspended among the DMF (8ml), add iodoethane (0.113mL, 1.42mmol).Reaction mixture stirs at ambient temperature and spends the night.After reaction mixture was evaporated to and does, resistates distributed between water and ethyl acetate.Organic layer washes with water, uses the salt water washing again, and through anhydrous sodium sulfate drying, concentrating under reduced pressure obtains title compound; 1H NMR (400MHz; CDCl 3) δ: 0.96 (3H, t), 1.25 (3H, t), 1.36-1.45 (2H, m), 1.72-1.76 (2H, m), 4.05-4.13 (4H, m), 5.50 (2H, s), 7.32-7.40 (5H, m), 7.52 (1H, s); M/z 327[MH +].
C) 3-butyl-1-ethyl-3,7-dihydro-1H-purine-2,6-diketone
With 3-butyl-1-ethyl-7-(phenyl methyl)-3,7-dihydro-1H-purine-2, (0.353g 1.08mmol) is dissolved in the acetate (30ml) the 6-diketone, adds 20% palladium hydroxide-carbon (0.238g), and mixture jolting under nitrogen atmosphere (50psi) is spent the night.Catalyzer passes through Celite
Figure A20081009925400622
Remove by filter, wash with acetate.Filtrate decompression concentrates and obtains title compound (0.227g, 89%); 1H NMR (400MHz; CDCl 3) δ: 0.97 (3H, t), 1.28 (3H, t), 1.38-1.47 (2H, m), 1.74-1.82 (2H, m), 4.12-4.17 (4H, m), 7.80 (1H, s); M/z 237[MH +].
D) 3-butyl-8-chloro-1-ethyl-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400623
With 3-butyl-1-ethyl-3,7-dihydro-1H-purine-2, the 6-diketone (100mg, 0.42mmol) and NCS (56mg 0.42mmol) is suspended among the MeCN (5ml), 120 ℃ of following carry out microwave radiation heating.Behind the reaction mixture concentrating under reduced pressure, separate title compound by using HPLC.[the HPLC condition that is used for purifying: 23 minute working time.The MeCN solution of solvent: 0.1%TFA and the aqueous solution of 0.1%TFA.MeCN rose to 95% linearly by 5% in 15 minutes.Remain on 95% and continue 2 minutes.Then 1 minute internal linear reduce to 5%, inject after 5 minutes in 5% balance next time.]； 1HNMR(400MHz；CDCl 3)δ：0.97(3H，t)，1.31(3H，t)，1.38-1.45(2H，m)，1.72-1.80(2H，m)，4.09-4.20(4H，m)，13.40(1H，br.s)；m/z?271[MH +]。
Embodiment 34: 8-chloro-3-(4-methyl amyl)-3,7-dihydro-1H-purine-2,6-diketone
Set out by 1-bromo-4-methylpentane (81mg)
By the MeOH recrystallization
Yield 34.8mg (29%), NMR; (400MHz, d 6-DMSO) δ H0.83 (d, 6H, J=8Hz), 1.12-1.22 (m, 2H), 1.55 (septet, 1H, J=8Hz), 1.58-1.68 (m, 2H), 3.83 (t, 2H, J=7.5Hz), 11.20 (s, 1H); M/z 271[MH +].
Embodiment 35: 6-(8-chloro-2,6-dioxo-1,2,6,7-tetrahydrochysene-3H-purine-3-yl)-2, the 2-dimethyl is own Nitrile
Figure A20081009925400632
By 6-bromo-2, the own nitrile of 2-dimethyl (100mg) sets out
By the MeOH recrystallization
Yield 48.5mg (35%); NMR; (400MHz, d 6-DMSO) δ H1.27 (s, 6H), 1.35-1.44 (m, 2H), 1.54-1.59 (m, 2H), 1.63-1.72 (m, 2H), 3.88 (t, 2H, J=7Hz), 11.24 (s, 1H); M/z 310[MH +].
Embodiment 36: 8-chloro-3-(6-methylheptyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400641
Set out by 1-bromo-6-methylheptane (95mg)
By the MeOH recrystallization
Yield 36mg (27%), NMR; (400MHz, d 6-DMSO) δ H0.83 (d, 6H, J=7.5Hz), 1.10-1.17 (m, 2H), 1.20-1.34 (m, 4H), 1.48 (septet, 1H, J=7.5Hz), 1.58-1.68 (m, 2H), 3.84 (t, 2H, J=8Hz), 11.22 (s, 1H); M/z 299[MH +].
Embodiment 37: 8-chloro-3-octyl group-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400642
With 8-chloro-3,7-dihydro-1H-purine-2,6-diketone (100mg, 0.44mmol) (52mg 0.49mmol) stirred 20 minutes in dry DMF (3ml), added 1-iodo-octane (118mg then with yellow soda ash, 0.49mmol), mixture is nitrogen atmosphere and 40 ℃ of following stirrings 65 hours.After being cooled to room temperature, mixture is by evacuated vessel and insert the thorough for several times degasification of nitrogen again.Adding tetrakis triphenylphosphine palladium (0) (102mg, 0.09mmol), mixture is degasification once more, and (0.385ml 4.4mmol), continues to stir 6.5 hours to add morpholine then.Add 2M HCl and EtOAc, filter two-phase system.Product mainly is included in the solid after the filtration, and it by THF-acetonitrile recrystallization, again by the MeOH recrystallization, is obtained pure title compound after the filtration.
Yield 48mg (36%); NMR; (400MHz, d 6-DMSO) δ H0.84 (t, 3H, J=7Hz), 1.18-1.30 (m, 10H), 1.57-1.66 (m, 2H), 3.84 (t, 2H, J=7.5Hz), 11.22 (s, 1H); M/z299[MH +].
Embodiment 38: 8-chloro-3-decyl-3,7-dihydro-1H-purine-2,6-diketone
(108mg) sets out by the 1-bromo-decane, according to the method preparation of embodiment 37.By by the MeOH recrystallization, the directed automated preparation of quality is carried out further purifying again.
Yield 2mg (1.4%); NMR; (400MHz, d 4-methyl alcohol) δ H0.89 (t, 3H, J=7Hz), 1.26-1.38 (m, 14H), 1.68-1.76 (m, 2H), 3.97 (t, 2H, J=7.5Hz); M/z 327[MH +].
Embodiment 39: 8-chloro-3-(cyclohexyl methyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400652
Set out by (brooethyl) hexanaphthene (87mg),, prepare according to the mode that is similar to embodiment 37 except 80 ℃ of extra down heating 18 hours.
By the MeOH recrystallization.
Yield 31mg (25%); NMR; (400MHz, d 6-DMSO) δ H0.90-1.02 (m, 2H), 1.08-1.20 (m, 3H), 1.53-1.69 (m, 5H), 1.77-1.87 (m, 1H), 3.70 (d, 2H, J=7.5Hz), 11.21 (s, 1H); M/z 283[MH +].
The general method of embodiment 40-46:
To 8-chloro-3,7-dihydro-1H-purine-2, (100mg adds alcohol (0.442mmol) to the 6-diketone in anhydrous THF (3ml) solution 0.442mmol).Mixture stirs down at 0 ℃, and (anhydrous THF (2ml) solution 0.88mmol) then dropwise added triphenylphosphine (232mg, anhydrous THF solution 0.88mmol) in 5 minutes for 280mg, 94% purity to add azo-2-carboxylic acid's dibenzyl ester simultaneously.After continuing 30 minutes under 0 ℃, at room temperature continue to stir 18 hours.Mixture is by finding time and recharge reactor degasification for several times with nitrogen, and (102mg, 0.088mmol), (0.385ml 4.42mmol), continues to stir 4.5 hours to add morpholine again to add tetrakis triphenylphosphine palladium (0) then.Add EtOAc and 2M HCl, mixture is removed the solid that yellow mercury oxide is separated out after filtering.Separating filtrate, organic phase is dissolved in the mixture that contains THF and MeOH after concentrating again.Above-mentioned solution by aminopropyl SPE, is used DCM-MeOH (1: the 1) eluant solution of THF-MeOH (1: 1), MeOH and 5%AcOH successively.After the resulting product partial concentration, obtain pure title compound by the MeOH recrystallization.
Embodiment 40: (+/-)-8-chloro-3-(3-methyl amyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400661
45mg sets out by (+/-)-3-methyl-1-pentene alcohol
Yield 20.2mg (17%); NMR; (400MHz, d 6-DMSO) δ H0.83 (t, 3H, J=7.5Hz), 0.90 (d, 3H, J=6.5Hz), 1.12-1.21 (m, 1H), 1.30-1.48 (m, 3H), 1.58-1.68 (m, 1H), 3.87 (t, 2H, J=7.5Hz), 11.21 (s, 1H); M/z 271[MH +].
Embodiment 41: 8-chloro-3-(2-cyclopentyl ethyl)-3,7-dihydro-1H-purine-2,6-diketone
50mg sets out by 2-cyclopentyl ethanol
Yield 24.6mg (20%); NMR; (400MHz, d 6-DMSO) δ H1.04-1.15 (m, 2H), 1.40-1.67 (m, 6H), 1.70-1.82 (m, 3H), 3.86 (t, 2H, J=7.5Hz), 11.22 (s, 1H); M/z283[MH +].
Embodiment 42: 8-chloro-3-(cyclopropyl methyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400671
32mg sets out by cyclopropyl-carbinol
Yield 22.3mg (21%); NMR; (400MHz, d 6-DMSO) δ H0.34-0.40 (m, 2H), 0.40-0.48 (m, 2H), 1.17-1.27 (m, 1H), 3.74 (d, 2H, J=7.5Hz), 11.23 (s, 1H); M/z241[MH +].
Embodiment 43: (+/-)-8-chloro-3-(2-methyl butyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400672
39mg sets out by (+/-)-2-methyl-1-butene alcohol
Yield 12mg (9.5%); NMR; (400MHz, d 6-DMSO) δ H0.81 (d, 3H, J=7Hz), 0.86 (t, 3H, J=7.5Hz), 1.06-1.17 (m, 1H), 1.30-1.41 (m, 1H), 1.90-2.00 (m, 1H), 3.68 (dd, 1H, J=13.5 and 8Hz), 3.75 (dd, 1H, J=13.5 and 7.5Hz), 11.22 (s, 1H); M/z257[MH +].
Embodiment 44: (+/-)-8-chloro-3-(2-methyl amyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400673
45mg sets out by (+/-)-2-methyl-1-pentene alcohol
Yield 22.4mg (19%); NMR; (400MHz, d 6-DMSO) δ H0.81 (d, 3H, J=7Hz), 0.84 (t, 3H, J=7.5Hz), 1.05-1.16 (m, 1H), 1.16-1.43 (m, 3H), 1.98-2.09 (m, 1H), 3.67 (dd, 1H, J=13.5 and 8Hz), 3.74 (dd, 1H, J=13.5 and 7Hz), 11.22 (s, 1H); M/z271[MH +].
Embodiment 45: 8-chloro-3-(cyclobutylmethyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400681
38mg sets out by cyclobutanemethanol
Yield 30.5mg (27%); NMR; (400MHz, d 6-DMSO) δ H1.73-1.85 (m, 4H), 1.86-1.97 (m, 2H), 2.66-2.79 (m, 1H), 3.90 (d, 2H, J=7.5Hz), 11.22 (s, 1H); M/z255[MH +].
Embodiment 46: 8-chloro-3-(cyclopentyl-methyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400682
44mg sets out by cyclopentyl carbinol
Yield 15mg (13%); NMR; (400MHz, d 6-DMSO) δ H1.20-1.32 (m, 2H), 1.42-1.54 (m, 2H), 1.54-1.66 (m, 4H), 2.32-2.45 (m, 1H), 3.79 (d, 2H, J=8Hz), 11.22 (s, 1H); M/z 269[MH +].
Embodiment 47: 8-chloro-3-(3-cyclopropyl propyl group)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400683
By 3-cyclopropyl-1-propyl alcohol (P.J.Wagner, J.Amer.Chem.Soc., 1981,103,3837-3841) (44mg) sets out
Yield 27.7mg (23%); NMR; (400MHz, d 6-DMSO) δ H-0.03-+0.03 (m, 2H), 0.34-0.40 (m, 2H), 0.65-0.75 (m, 1H), 1.15-1.23 (m, 2H), 1.66-1.76 (m, 2H), 3.87 (t, 2H, J=7Hz), 11.15 (s, 1H); M/z 269[MH +].
Embodiment 48: 8-chloro-3-(2-cyclobutyl ethyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400691
By 2-cyclobutyl ethanol (P.Vergnon, Eur.J.Med.Chem., 1975,10,65-71) (44mg) sets out
Yield 21.5mg (18%); NMR; (400MHz, d 6-DMSO) δ H1.53-1.64 (m, 2H), 1.68-1.85 (m, 4H), 1.93-2.03 (m, 2H), 2.19-2.30 (m, 1H), 3.78 (t, 2H, J=7Hz), 11.20 (s, 1H); M/z 269[MH +].
Embodiment 49: 8-chloro-3-(4-fluorine butyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400692
A) 8-chloro-3-(4-fluorine butyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400693
In being equipped with the 1.5ml microwave bottle of agitator, to 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (200mg, 0.88mmol, add in anhydrous DMSO (1ml) solution 1eq) sodium bicarbonate (113mg, 1.07mmol, 1.2eq), add 1-bromo-4-fluorine butane (114 μ l again, 165mg, 1.06mmol, 1.2eq).After the bottle sealing, use the microwave stirring heating, keeping temperature is 120 ℃, continues 25 minutes, and peak power is output as 300W.Resulting dark brown solution by the directed automated preparation HPLC of quality purifying, obtains the title compound (159mg, 60%) into white solid with methyl alcohol (1ml) dilution.m/z?301.3[MH +]。
8-chloro-3-(4-fluorine butyl)-3,7-dihydro-1H-purine-2,6-diketone
To 8-chloro-3-(4-fluorine butyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (100mg, 0.33mmol, add tetrakis triphenylphosphine palladium (0) (38mg, 0.033mmol in anhydrous DCM (2ml) suspension 1eq), 10%bw), add acetate (115 μ l, 121mg, 2.01mmol again, 6eq) and phenyl silane (410 μ l, 360mg, 3.33mmol, 10eq).Resulting pale yellow solution stirred 16 hours at ambient temperature, obtained mulberry solution.Except that after desolvating, the resistates heating for dissolving is in DMSO/ methanol solution (3ml, 2: 1) under nitrogen gas stream.Make gelatinous mixture be cooled to envrionment temperature, filter the back, obtain title compound (35mg, 43%) into white solid by the directed automated preparation HPLC of quality purifying.M/z 261.2[MH +] NMR (400MHz, MeOD), δ H(4.45 2H, dt, J=47 and 6Hz), 4.03 (2H, t, J=7Hz), 1.90-1.65 (4H, m).
Following compound prepares in a comparable manner, simultaneously suitably by preparation property or the directed automated preparation HPLC of quality purifying:
Embodiment 50: 8-chloro-3-(3-fluoropropyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400701
NMR (400MHz, MeOD), δ H(4.51 2H, dt, J=47 and 6Hz), 4.11 (2H, t, J=7Hz), 2.18-2.03 (2H, m).m/z?247[MH +]。
Embodiment 51: 8-chloro-3-(5-fluorine amyl group)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400711
NMR (400MHz, MeOD), δ H(4.41 2H, dt, J=48 and 6Hz), 3.99 (2H, t, J=8Hz), 1.84-1.63 (4H, m), 1.52-1.40 (2H, m).m/z?273.29[MH -]。
Embodiment 52: 3-(the 3-butene-1-yl)-8-chloro-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400712
With 8-chloro-3,7-dihydro-1H-purine-2,6-diketone (100mg, 0.44mmol) (52mg 0.49mmol) stirred 45 minutes in dry DMF (3ml), added 4-bromo-1-butylene (66mg then with yellow soda ash, 0.49mmol), mixture is nitrogen atmosphere and 40 ℃ of following stirrings 65 hours.After being cooled to room temperature, mixture recharges the thorough for several times degasification of nitrogen by evacuated vessel.Adding tetrakis triphenylphosphine palladium (0) (102mg, 0.09mmol), mixture is degasification once more, and (0.385ml 4.4mmol), continues to stir 6.5 hours to add morpholine then.Add 2M HCl and EtOAc, filter two-phase system and remove the yellow solid that precipitation is separated out.The organic phase of filtrate is separated the back evaporation.Be dissolved among the THF-MeOH (1: 1) resistates is warm, be seated on the aminopropyl SPE (5g), use MeOH-DCM (1: the 1) eluant solution of THF-MeOH (1: 1), MeOH and 5%AcOH successively.The product part further by the directed automated preparation purifying of quality, obtains title compound.
Yield 27.5mg (26%), NMR; (400MHz, d 6-DMSO) δ H(2.40 dt, 2H, J=7 and 6Hz), 3.93 (t, 2H, J=7Hz), 4.97-5.07 (m, 2H), 5.74-5.85 (m, 1H), 11.22 (s, 1H); M/z 241[MH +].
Embodiment 53: 8-chloro-3-(6-fluorine hexyl)-3,7-dihydro-1H-purine-2,6-diketone
NMR (400MHz, MeOD), δ H4.40 (2H, dt, 48 and 6Hz), 3.98 (2H, t, 8Hz), 1.80-1.60 (4H, m), 1.52-1.35 (4H, m).m/z?287[MH -]。
Embodiment 54: 8-chloro-3-ethyl-1-methyl-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-3-({ [2-(methoxyl group) ethyl] oxygen base } methyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
To 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (6g, add in dry DMF 26.5mmol) (30ml) solution yellow soda ash (3.09g, 29.15mmol).After at room temperature stirring 10 minutes, (3.03ml 26.5mmol), continues to stir 66 hours under nitrogen atmosphere and room temperature to add the methoxy ethoxy Methochloride.Behind the reaction mixture vacuum concentration, resistates is dissolved among the EtOAc (100ml),, aqueous extract is extracted dry organic extract (MgSO with DCM (100ml) with salt solution (100ml) washing 4), merge final vacuum and concentrate.Resistates leaches solid after grinding with EtOAc.Filtrate concentrating obtains light brown oily matter, and it is adsorbed on the silicon-dioxide, and (Si, 50g) purifying with 1: 1 EtOAc/ hexanaphthene-EtOAc wash-out of gradient, obtain the title compound (2g, 24%) into white solid, m/z 315.2[MH by SPE +].
B) 8-chloro-1-methyl-3-({ [2-(methoxyl group) ethyl] oxygen base } methyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400731
To 8-chloro-3-({ [2-(methoxyl group) ethyl] oxygen base } methyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (2g, add in dry DMF 6.37mmol) (15ml) solution yellow soda ash (0.743g, 7mmol).After at room temperature stirring 10 minutes, (0.44ml 7mmol), continues to stir 18 hours under nitrogen atmosphere and room temperature to add the methyl iodide.Behind the reaction mixture vacuum concentration, resistates is dissolved among the EtOAc (100ml), with salt solution (100ml) washing.Dry organic extract (MgSO 4), filter and evaporation obtain into tawny oily matter title compound (85% purity) (2.98g, quantitatively), m/z 329.2[MH +].
C) 8-chloro-1-methyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400732
To 8-chloro-1-methyl-3-({ [2-(methoxyl group) ethyl] oxygen base } methyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (2.9g 6.37mmol) adds the 5M HCl aqueous solution (20ml) to the 6-diketone in the solution of Zai diox (20ml) and water (20ml).The heating 18 hours under 100 ℃ and nitrogen atmosphere of resulting mixture.Reaction mixture is vacuum concentration subsequently, and resistates is dissolved among the EtOAc (100ml), washes with water.Dry organic extract (MgSO 4), filter and evaporation.(Si, 20g) purifying with 2: 3 EtOAc/ hexanaphthene wash-outs, obtain the title compound (1.04g, 68%) into white solid by SPE.m/z?241.1[MH +]。
D) 8-chloro-3-ethyl-1-methyl-3,7-dihydro-1H-purine-2,6-diketone
Figure A20081009925400733
To 8-chloro-1-methyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (100mg, 0.42mmol) dry DMF (3ml) solution in add yellow soda ash (58mg, 0.54mmol), stir after 10 minutes, add ethyl iodide (0.043ml, 0.54mmol), reaction mixture stirred 90 hours under room temperature and nitrogen atmosphere.Add Pd (PPh subsequently 3) 4(73mg, 0.063mmol), reactor is found time the back with nitrogen wash (x3), add morpholine (0.37ml, 4.3mmol) and under room temperature and nitrogen atmosphere, continue to stir 4 hours.Reaction mixture is with EtOAc (25ml) dilution, with the 2M HCl aqueous solution (25ml) washing.Dry organic extract (MgSO 4), filter and evaporation.Go up purifying by compound being seated in aminopropyl SPE (5g), after the MeOH washing, product 5%AcOH/MeOH wash-out obtains the title compound (67mg, 70%) into white solid.NMR；d H(400MHz，d 6-DMSO)1.20(t，3H，J＝7Hz)，3.22(s，3H)，3.97(q，2H，J＝7Hz)，14.46(1H，br?s)；m/z?227.2[M-H] -。
At these whole publications of being quoted in this specification sheets, include, but are not limited to various patents and patent application and be incorporated herein by reference, just look like every piece of full content in the independent publication by specifically with independently be incorporated herein by reference the same.

Claims (13)

1. formula (I) compound or its pharmacologically acceptable salts or solvate,
Figure A20081009925400021
Wherein
R 1Be selected from: hydrogen and methyl;
R 2Expression is by C 3-6The C of cycloalkyl substituted 1-4Alkyl;
And R 3Expression chlorine.
2. according to the compound of claim 1, it is used for people or veterinary drug.
3. according to the compound of claim 1, it is used for the treatment of the lipid metabolism obstacle.
4. according to the compound of claim 1, it is used for the treatment of the diabetes dyslipidemia, mixes dyslipidemia, heart failure, hypercholesterolemia disease, atherosclerosis, arteriosclerosis, and hypertriglyceridemia, type ii diabetes, type i diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, stenocardia, chronic renal failure, peripheral vascular disease or apoplexy.
5. according to the compound of claim 1, it is used for the treatment of dyslipidemia, hyperlipoproteinemia, hypercholesterolemia disease or hypertriglyceridemia.
6. be used for the treatment of purposes in the medicine of human or animal's object according to the compound of claim 1 in preparation, described human or animal's object suffers from by the not enough caused disease of HM74A receptor activation or benefits from the disease that activates this receptor.
7. be used for the treatment of purposes in the medicine of lipid metabolism obstacle according to the compound of claim 1 in preparation.
8. the compound according to claim 1 is used for the treatment of the diabetes dyslipidemia in preparation, mixes dyslipidemia, heart failure, hypercholesterolemia disease, atherosclerosis, arteriosclerosis, and hypertriglyceridemia, type ii diabetes, type i diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, stenocardia, the purposes in the medicine of chronic renal failure or apoplexy.
9. the compound according to claim 1 is used for the treatment of dyslipidemia in preparation, hyperlipoproteinemia, the purposes in the medicine of hypercholesterolemia disease or hypertriglyceridemia.
10. pharmaceutical preparation, it contains compound and one or more physiology acceptable diluent, vehicle or the carrier of with good grounds claim 1.
11. combination is used for together or respectively, order or administration simultaneously separately or the pharmaceutical preparation of merging form, described combination comprises according to the compound of claim 1 and other therapeutic activity medicine.
12. pharmaceutical preparation comprises
(i) according to the compound of claim 1;
(ii) one or more are selected from the activeconstituents in statins, the special class of shellfish, bile acide binding resin and the nicotinic acid; And
(iii) acceptable diluent, vehicle or carrier on one or more physiology.
13. preparation is according to the method for the compound of claim 1, this method comprises:
(i) alkylation, perhaps dialkyl groupization on N1 and N3 on the xanthic N1 of N7 protection or N3;
(ii) chlorination on C8; And
(iii) deprotection base;
Can be with any order, condition is to carry out the deprotection base after alkylation.
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