CN101087790A - Xanthine derivatives with hm74a receptor activity - Google Patents

Xanthine derivatives with hm74a receptor activity Download PDF

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CN101087790A
CN101087790A CN 200580044356 CN200580044356A CN101087790A CN 101087790 A CN101087790 A CN 101087790A CN 200580044356 CN200580044356 CN 200580044356 CN 200580044356 A CN200580044356 A CN 200580044356A CN 101087790 A CN101087790 A CN 101087790A
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aryl
heteroaryl
alkyl
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理查德·J·D·哈特利
伊万·L·平托
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SmithKline Beecham Corp
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Abstract

The present invention relates to therapeutically active compounds of formula (I) 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.

Description

Xanthine derivative 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.
Hyperlipemia (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 hyperlipemia and causing thus is the special class (fibrates) of statins (statins), chlorine shellfish, bile acide binding resin (bile acid bindingresin) and nicotinic acid.Nicotinic acid (Niacin, vitamins B) be used for the treatment of clinically the patient who suffers from multi-form hyperlipemia 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.
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 the xanthine derivative of therapeutic activity and described derivative treatment, particularly in treatment by the not enough caused disease of HM74A receptor activation or benefit from purposes in the disease that activates this receptor; particularly lipid metabolism disease of described disease comprises hyperlipemia or hyperlipoproteinemia for example diabetes hyperlipemia and mixing hyperlipemia (mixed dyslipidaemia); in heart failure; hypercholesterolemia (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, we provide at least a chemical entity in the formula that is selected from (I) compound and the pharmaceutically acceptable derivates thereof.
Figure A20058004435600111
Wherein:
R 1Representative is selected from following group: hydrogen, C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl and-(alkylidene group (alk)) m-X-(alkylidene group) n-Y,
Wherein X represents A, A1, A2 or direct key;
A representative is selected from following group: cycloalkylidene, inferior cycloalkenyl group, aryl, heteroaryl, heterocyclic radical ,-CH 2-OC (O)-;
The A1 representative is selected from following group :-CH 2-O-(CH 2) qAryl-O-,-CH 2-O-(CH 2) wN (R 5) C (O) O-,-CH 2-N (R 5) C (O) O-,-CH 2-N (R 5) C (O)-,-CH 2-(O) p-(CH 2) qC (O) NR 5-,-CH 2-N (R 5) C (O) N (R 5)-,-CH 2-C (O) N ((CH 2) wOH)-,-CH 2-NR 5-S (O) 2-, CH 2-S (O) 2NR 5-,-CH 2-C (O) O-,-O-,-NR 5-,-S-;
A2 representative :-CH (OH)-;
When X was A, A1 or A2, Y representative was selected from following group: heteroaryl, heterocyclic radical, aryl, cycloalkyl, cycloalkenyl group ,-O (CH 2) n-aryl ,-C (O) O-aryl ,-CH (aryl) 2,-CH (heteroaryl) 2,-C 1-6Haloalkyl ,-C (O) R 4,-NR 5R 7,-C (O) NR 5R 7,-NR 5C (O) R 7,-NR 5C (O) OR 7,-C (O) (CH 2) qOR 4, halogen, cyano group ,-N (R 5) C (O) OR 7,-OC (O) NR 5R 6,-NR 5C (O) R 8,-OR 5,-OC (O) R 4
When X was A1, Y was selected from :-O (CH 2) n-aryl ,-the O-heteroaryl ,-OR 5,-OC (O) R 5,-NH-aryl ,-OC (O) NR 5R 6,
N is selected from 2,3,4 and 5 integer;
When X was A1, Y was-CF 3, or when X was A2, n was selected from 1,2,3,4 and 5 integer;
When X was direct key, the Y representative was selected from following group :-C (O) (CH 2) qOR 5,-C (O)-aryl ,-C (O)-heteroaryl ,-C (O)-heterocyclic radical ,-heteroaryl ,-heterocyclic radical ,-aryl ,-cycloalkyl ,-cycloalkenyl group ,-C 1-6Haloalkyl ,-halogen ,-cyano group, 3 or 4 the ring condense system ,-CH (aryl) 2,-CH (heteroaryl) 2,-OR 5,-NR 5R 7,-NCOOR 8,-(O) pC (O) NR 5R 6,-NR 5C (O) R 8,-OR 5,-(O) pC (O) R 4
When Y contained ring, this ring can be chosen wantonly by one or more following groups and replace: C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, halogen ,-NH 2, (CH 2) q-NR 5R 7,-(CH 2) q-(O) p-(CH 2) q-N (R 5) C (O) OR 8,-(CH 2) q-N (R 5) C (O) R 8,-(CH 2) q-(O) p-(CH 2) q-C (O) NR 5R 6,-(CH 2) q-N (R 5) C (O) N (R 5) R 6,-(CH 2) q-C (O) N ((CH 2) mOH) R 5,-(CH 2) q-N (R 5)-S (O) 2R 8,-CH 2-S (O) 2N (R 5) R 6,-C 1-6Haloalkyl ,-OCF 3,-OCH (F) 2,-OCH 2F ,-COOR 5,-OR 5,-(R 8) pCN ,-S (O 2) R 9,-(CH 2) nHeteroaryl ,-(CH 2) nHeterocyclic radical ,-(CH 2) nCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) nAryl;
R 2Be selected from: hydrogen; Or C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl, its each can choose wantonly and replace by one or more following groups: C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, C 1-6Haloalkyl, halogen ,-CN ,-OR 4,-(CH 2) nCOR 4,-C (O) OR 4,-OCOR 4,-(CH 2) nNR 5R 6,-(NH) pCONR 5R 6,-OCONR 5R 7With-NHC (O) OR 7
R 3Be selected from: halogenated C 1-6Alkyl;
R 4Be selected from: hydrogen, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) nCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) nHeterocyclic radical ,-(CH 2) nAryl and-(CH 2) nHeteroaryl;
R 5And R 6Be selected from: hydrogen and C 1-4Alkyl;
R 7Be selected from: hydrogen, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) tCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) tHeterocyclic radical ,-(CH 2) tAryl and-(CH 2) tHeteroaryl;
R 8Be selected from C 1-4Alkyl;
R 9Be selected from C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) nCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) nHeterocyclic radical ,-(CH 2) nAryl and-(CH 2) nHeteroaryl, CN;
The m representative is selected from following integer: 0,1,2,3,4 and 5;
The n representative is selected from following integer: 0,1,2,3,4 and 5;
The p representative is selected from following integer: 0 and 1;
The q representative is selected from following integer: 0,1 and 2;
The t representative is selected from following integer: 1 and 2;
The w representative is selected from following integer: 2,3 and 4.
Condition is:
I) work as R 1Represent hydrogen or C 1-3During alkyl, R 2Be different from R 1
Ii) work as R 1Represent ethyl, and R 3Represent CF 3The time, R 2Not CH 2-CH=CH 2With
Iii) work as R 1Represent methylidene, and R 3Represent CF 3The time, R 2It or not isobutyl-.
In one embodiment of the invention, we provide at least a chemical entity in the formula that is selected from (I) compound and the pharmaceutically acceptable derivates thereof:
Figure A20058004435600131
Wherein:
R 1Represent hydrogen or be selected from following group: C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl ,-(CH 2) nCycloalkyl ,-(CH 2) nHeterocyclic radical ,-(CH 2) nAryl and-(CH 2) nHeteroaryl, its each can choose wantonly and replace by one or more following groups :-(CH 2) nCycloalkyl ,-(CH 2) nHeterocyclic radical ,-(CH 2) nAryl ,-(CH 2) nHeteroaryl, C 1-6Haloalkyl, halogen, cyano group ,-OR 4,-(CH 2) nCOR 4,-CO 2R 4,-OCOR 4,-(CH 2) nNR 5R 7,-(NH) mCONR 5R 7,-OCONR 5R 7With-NHCO 2R 7
R 2Be selected from: C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl ,-(CH 2) nCycloalkyl ,-(CH 2) nHeterocyclic radical ,-(CH 2) nAryl and-(CH 2) nHeteroaryl, its each can choose wantonly and replace by one or more following groups: cycloalkyl, heterocyclic radical, aryl, heteroaryl, C 1-6Haloalkyl, halogen, cyano group ,-OR 4,-(CH 2) nCOR 4,-CO 2R 4,-OCOR 4,-(CH 2) nNR 5R 6,-(NH) mCONR 5R 6,-OCONR 5R 7With-NHCO 2R 7
R 3Be selected from: halogenated C 1-6Alkyl;
R 4Be selected from: hydrogen, C 1-6Alkyl C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) nCycloalkyl ,-(CH 2) nHeterocyclic radical ,-(CH 2) nAryl and-(CH 2) nHeteroaryl;
R 5And R 6Be independently selected from: hydrogen and C 1-4Alkyl;
R 7Be selected from: hydrogen, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) pCycloalkyl ,-(CH 2) pHeterocyclic radical ,-(CH 2) pAryl and-(CH 2) pHeteroaryl;
The n representative is selected from following integer: 0,1,2,3 and 4;
The m representative is selected from following integer: 0 and 1;
The p representative is selected from following integer: 1 and 2.
Condition is:
I) work as R 1Represent H or C 1-3During alkyl, R 2Be different from R 1
Ii) work as R 1Represent ethyl, and R 3Represent CF 3The time, R 2Not CH 2-CH=CH 2With
Iii) work as R 1Represent methylidene, and R 3Represent CF 3The time, R 2It or not isobutyl-.
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 or integer.
Term as used herein " halogen " or " halo " 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 as used herein " alkenyl " is meant and contains the carbon atom that specifies number, the straight or branched hydrocarbon chain that contains one or more pairs of keys.Suitable example includes but not limited to vinyl, 2-propenyl, 3-butenyl, crotyl, pentenyl, 3-pentenyl, 3-methyl-2-butene base, 3-hexenyl etc.
Term as used herein " alkynyl " is meant and contains the carbon atom that specifies number, contains one or more triple-linked straight or branched hydrocarbon chains.Suitable example includes but not limited to ethynyl, proyl, ethyl acetylene base, 1-pentynyl, 3-methyl isophthalic acid-butynyl etc.
Term as used herein ' C 1-6Haloalkyl ' be meant as defined C in the literary composition 1-6Alkyl, wherein at least one hydrogen atom is replaced by halogen.This examples of groups comprises fluoro ethyl, trifluoromethyl or trifluoroethyl etc.
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 ' cycloalkylidene ' is meant that 3-8 carbon connects the saturated monocyclic hydrocarbon ring of base.This examples of groups comprises cyclopropylidene, inferior cyclobutyl, cyclopentylidene, cyclohexylidene, inferior suberyl or inferior ring octyl group etc.
Term as used herein ' cycloalkenyl group ' is meant the monocyclic hydrocarbon ring of the unsaturated non-fragrance of 3 to 8 carbon atoms that contain one or more carbon-to-carbon double bonds.This examples of groups comprises cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctene base etc.
Term as used herein ' inferior cycloalkenyl group ' is meant the monocyclic hydrocarbon ring of the unsaturated non-fragrance of 3 to 8 carbon linking groups that contain one or more carbon-to-carbon double bonds.This examples of groups comprises inferior cyclopropenyl radical, inferior cyclobutene base, cyclopentenylidene, phenylidene, inferior cycloheptenyl or inferior cyclooctene base etc.
Term as used herein " aryl " is meant 5 or 6 Yuans monocyclic aromatic group, or condensed 8-10 person two cyclophane perfume base groups, and wherein at least one ring has conjugated πDian Zi system, contains up to two conjugation or condensed ring system." aryl " comprises isocyclic aryl and dibenzyl.Suitable example includes but not limited to phenyl, naphthyl etc.
Term used herein " heteroaryl " is meant and contains 5 or 6 Yuans mono-cyclic aromatic group or the condensed 8-10 person bicyclic aromatic group that 1-3 is independently selected from oxygen, nitrogen and sulfur heteroatom, it has at least one ring that contains conjugated πDian Zi system, contains up to two conjugation or condensed ring system.The suitable example of this monocyclic aromatic ring includes but not limited to thienyl, furyl, pyrryl, triazolyl, imidazolyl,  azoles base, thiazolyl,  di azoly, isothiazolyl, different  azoles base, thiadiazolyl group, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl and pyridyl.The suitable example of this fused aromatic ring includes but not limited to benzo-fused aromatic ring for example quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, cinnolines base, naphthyridine base (naphthyridinyl), indyl, indazolyl, pyrrolopyridinyl, benzofuryl, benzothienyl, benzimidazolyl-, benzoxazol base, benzisoxa  azoles base, benzothiazolyl, benzisothiazole base, benzo  di azoly, diazosulfide base etc.
Term as used herein " heterocyclic radical " is meant 5 or 6 Yuans saturated cyclic hydrocarbon group, and it contains 1 to 3 heteroatoms that is independently selected from oxygen, nitrogen and sulphur.Suitable example includes but not limited to pyrrolidyl, morpholinyl, imidazolidyl and piperazinyl.
Term as used herein ' 3 or 4 rings condense system ' be meant condensed 12-18 person three ring or Fourth Rings, it contains the heteroatoms of 1 to 4 N, and wherein at least one ring is aromatic ring.On ring carbon atom, can have one or more optional oxygen substituting groups.The example of this condensed aromatic ring comprises carbazyl, acenaphthenyl, naphthothiazoles base etc.
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.
Term as used herein " pharmaceutically acceptable derivates " is meant any pharmaceutically acceptable derivates of The compounds of this invention, for example salt, solvate or ester, it can (directly or indirectly) provide formula (I) compound or its active metabolite or resistates after delivering medicine to Mammals such as people.These derivatives are conspicuous to those skilled in the art, do not need the over-drastic experiment, and with reference to Burger ' s Medicinal Chemistry And Drug Discovery, 5 ThEdition, the instruction of Vol 1:Principles and Practice, it is hereby incorporated by.
What it should be understood by one skilled in the art that is, compound of the present invention can be modified obtaining its pharmaceutically acceptable derivates it on any functional group of compound, and compound of the present invention can carry out above-mentioned modification on a more than position.
In one embodiment, " pharmaceutically acceptable derivates " is meant salt or solvate.
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 of patient's administration, be meant with this pharmaceutical preparation in can accept and the composition nontoxic aspect other components compatibility arbitrarily its recipient.
Term as used herein " solvate " is meant by what solute (being formula (I) compound, its salt or its pharmaceutically acceptable derivates in the present invention) and solvent formed to have a variable stoichiometric complex compound.This kind solvent that satisfies the object of the invention can not disturb the biological activity of described solute.Solvent for use can be pharmaceutically acceptable solvent.The example of suitable pharmaceutically acceptable solvent comprises water, ethanol and acetate.The example of spendable 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 pharmacy acceptable salt or solvate.Yet other salt or solvate can be used in the preparation of formula (I) compound for example or its pharmacy acceptable salt or solvate.
Pharmacy acceptable salt comprises Berge, Bighley and Monkhouse, J.Pharm.Sci., 1977,66, the salt described in the 1-19.Suitable pharmacy acceptable salt comprises by adding for example an alkali metal salt that forms of alkali metal hydroxide of alkali metal base.The example of suitable an alkali metal salt is sodium salt or sylvite.Other suitable pharmacy 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.
Compound treatment by the HM74A receptor activation not enough caused disease or benefit from purposes in the disease that activates the HM74A acceptor; particularly lipid metabolism disease of described disease comprises hyperlipemia or hyperlipoproteinemia for example diabetes hyperlipemia (diabetic dyslipidemia) and mixing hyperlipemia; in heart failure; hypercholesterolemia, cardiovascular disorder comprise atherosclerosis, arteriosclerosis and hypertriglyceridemia.Find that also The compounds of this invention equally also can be used as coronary artery disease, 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.Find that The compounds of this invention can be used as agonist or the partial agonist of HM74A equally.
The compounds of this invention is in treatment and alleviate in many lipid metabolism disease symptomses and have the potential result of treatment; described disease comprises hyperlipemia or hyperlipoproteinemia for example diabetes hyperlipemia and mixing hyperlipemia; heart failure, hypercholesterolemia, cardiovascular disorder comprise atherosclerosis, arteriosclerosis and hypertriglyceridemia; type ii diabetes; type i diabetes, insulin resistance, hyperlipidaemia; anorexia nervosa, obesity.Find that also 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, also 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).
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.
Nicotinic acid has significant side effects, and this may be because 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 demonstrates side effect lower for nicotinic acid.Identified that HM74A is the high-affinity receptor of nicotinic acid, and HM74 is a low-affinity receptor.Find the HM74A agonist or the partial agonist of The compounds of this invention useful as selective; 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 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 (confluence) (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 is 48 hours results (harvested) after transfection.By with 50ngml -1In substratum, replenished 16 hours, carry out the Toxins, pertussis treatment.All transient transfection research relates to acceptor and G I/oG albumen, 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-12 HAM substratum 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 substratum.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 (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 precipitation (pellet) is suspended in 10mM Tris-HCl and the 0.1 mM EDTA of 1ml once more, among the pH7.5 (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 precipitation, 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-orifice plate at room temperature GTP γ S for Wieland, T. and Jakobs according to previous described method.Briefly, the diluent of preparation standard or test compounds is that 10 μ l are added in the 384-orifice plate with volume then.(HM74A or HM74 alkene are released at assay buffer (20mM HEPES, 100mM NaCL, 10mM MgCl with film 2, pH7.4) in, it is 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]-(1170 Ci/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 incubation 4 hours at room temperature.When incubation period finishes, at Leadseeker machine (VIEWLUXPLUS; Perkin-Elmer) read plate on, measure specificity in conjunction with level.
Improve these tests by reducing final test volume to 10 μ l.For the test of this 10 μ l, use the scheme of revising.This comprises standard model or the test compounds of only using in each hole of 384-orifice plate to 100nl, and 1.5 μ g films and 100 μ g Leadseeker WGA pearls.For low volume scheme, with film, pearl and [ 35S]-GTP γ S is admixed together, and then this mixture of 10 μ l is assigned in each hole.Incubation is with to read plate identical with the test of 10 μ l and 50 μ l.
With all exemplary compounds one or two is above-mentioned [ 35S]-GTP γ S tests in (i.e. the test of 10 μ l and 50 μ l) in conjunction with test.
Use the XC50 software package, with four parameter logical equatiions carry out curve fitting (2 points of deletion maximum from arbitrary curve) come analytical data.Use pEC with respect to nicotinic acid bonded peak response 50Render a service with % and to represent the specificity combination.
In vivo test
Before research, test the HM74A agonist at least 12 hours the male Spague-Dawley rat (200-250 g) of fasting.Compound by intravenously with the dosage of 1mg/kg or 3mg/kg (5ml/kg) or through the dosed administration of feeding,mouth with 1-30mg/kg (10ml/kg).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 (Becton Dickinson Microtainer, PST LH), and centrifugal (10,000g, 5 minutes) obtain plasma sample.The test kit that use is purchased (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, it can be delivered medicine to clear-headed cavy.Before testing, make male Dunkin Hartley cavy (300-600g; N=10-20 only/group) fasting 12 hours, but be no more than 24 hours.Under restorative anesthesia (isoflurane 3.5% (1L/min) that contains other O2), study preceding blood sample (0.5ml) by gathering in every animal by cardiac puncture.Place infrared temperature sensor at the left ear place of every animal and carry out ear temperature mensuration.In preceding 5 minutes of administration timed interval of 30 minutes to the administration, temperature measurement result of each minute record.After administration 2 hours then, temperature measurement result of 15 minutes records at interval.Animal through port feeding is accepted test compounds (5ml/kg).Under lethality (terminal) anesthesia, by cardiac puncture blood sample collection (0.5ml).After administration 0.5,1,2,3 and 4 hour from each animal blood sample collection so that data to be provided.All blood samples are placed blood cylinder (roller) last 5 minute, preserve on ice then until research and finish.Centrifugation (12000g, 5min) after, blood plasma is transferred in the new test tube, and is preserved down until measuring NEFA concentration at-20 ℃.
Synthetic compound (referring to following synthetic embodiment) according to formula (I), and above-mentioned [ 35S]-GTP γ S in conjunction with the test in test.All embodiment compounds all have 4.3 or higher pEC50 and 30% or higher effectiveness (with respect to nicotinic acid).
Discoverable type (I) compound can be used for people's medicine or veterinary drug, particularly is used to control hyperlipemia and hyperlipoproteinemia as the HM74A activator.
According to a further aspect in the invention, provide at least a chemical entity in the formula that is selected from (II) compound and the pharmaceutically acceptable derivates thereof,
Figure A20058004435600211
Wherein:
R 1Representative is selected from following group: hydrogen, C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl and-(alkylidene group) m-X-(alkylidene group) n-Y,
Wherein X represents A, A1, A2 or direct key;
A representative is selected from following group: cycloalkylidene, inferior cycloalkenyl group, aryl, heteroaryl, heterocyclic radical ,-CH 2-OC (O)-;
The A1 representative is selected from following group :-CH 2-O-(CH 2) qAryl-O-,-CH 2-O-(CH 2) wN (R 5) C (O) O-,-CH 2-N (R 5) C (O) O-,-CH 2-N (R 5) C (O)-,-CH 2-(O) p-(CH 2) qC (O) NR 5-,-CH 2-N (R 5) C (O) N (R 5)-,-CH 2-C (O) N ((CH 2) wOH)-,-CH 2-NR 5-S (O) 2-, CH 2-S (O) 2NR 5-,-CH 2-C (O) O-,-O-,-NR 5-,-S-;
A2 representative :-CH (OH)-;
When X was A, A1 or A2, Y representative was selected from following group: heteroaryl, heterocyclic radical, aryl, cycloalkyl, cycloalkenyl group ,-O (CH 2) n-aryl ,-C (O) O-aryl ,-CH (aryl) 2,-CH (heteroaryl) 2,-C 1-6Haloalkyl ,-C (O) R 4,-NR 5R 7,-C (O) NR 5R 7,-NR 5C (O) R 7,-NR 5C (O) OR 7,-C (O) (CH 2) qOR 4, halogen, cyano group ,-N (R 5) C (O) OR 7,-OC (O) NR 5R 6,-NR 5C (O) R 8,-OR 5,-OC (O) R 4
When X was A1, Y was selected from :-O (CH 2) n-aryl ,-the O-heteroaryl ,-OR 5,-OC (O) R 5,-NH-aryl ,-OC (O) NR 5R 6,
N is selected from 2,3,4 and 5 integer;
When X was A1, Y was-CF 3, or when X was A2, n was selected from 1,2,3,4 and 5 integer;
When X was direct key, the Y representative was selected from following group :-C (O) (CH 2) qOR 5,-C (O)-aryl ,-C (O)-heteroaryl ,-C (O)-heterocyclic radical ,-heteroaryl ,-heterocyclic radical ,-aryl ,-cycloalkyl ,-cycloalkenyl group ,-C 1-6Haloalkyl ,-halogen ,-cyano group, 3 or 4 the ring condense system ,-CH (aryl) 2,-CH (heteroaryl) 2,-OR 5,-NR 5R 7,-NCOOR 8,-(O) pC (O) NR 5R 6,-NR 5C (O) R 8,-OR 5,-(O) pC (O) R 4
When Y contained ring, this ring can be chosen wantonly by one or more following groups and replace: C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, halogen ,-NH 2, (CH 2) q-NR 5R 7,-(CH 2) q-(O) p-(CH 2) q-N (R 5) C (O) OR 8,-(CH 2) q-N (R 5) C (O) R 8,-(CH 2) q-(O) p-(CH 2) q-C (O) NR 5R 6,-(CH 2) q-N (R 5) C (O) N (R 5) R 6,-(CH 2) q-C (O) N ((CH 2) mOH) R 5,-(CH 2) q-N (R 5)-S (O) 2R 8,-CH 2-S (O) 2N (R 5) R 6,-C 1-6Haloalkyl ,-OCF 3,-OCH (F) 2,-OCH 2F ,-COOR 5,-OR 5,-(R 8) pCN ,-S (O 2) R 9,-(CH 2) nHeteroaryl ,-(CH 2) nHeterocyclic radical ,-(CH 2) nCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) nAryl;
R 2Be selected from: hydrogen; Or C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl, its each can choose wantonly and replace by one or more following groups: C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, C 1-6Haloalkyl, halogen ,-CN ,-OR 4,-(CH 2) nCOR 4,-C (O) OR 4,-OCOR 4,-(CH 2) nNR 5R 6,-(NH) pCONR 5R 6,-OCONR 5R 7With-NHC (O) OR 7
R 3Be selected from: halogenated C 1-6Alkyl;
R 4Be selected from: hydrogen, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) nCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) nHeterocyclic radical ,-(CH 2) nAryl and-(CH 2) nHeteroaryl;
R 5And R 6Be selected from: hydrogen and C 1-4Alkyl;
R 7Be selected from: hydrogen, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) tCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) tHeterocyclic radical ,-(CH 2) tAryl and-(CH 2) tHeteroaryl;
R 8Be selected from C 1-4Alkyl;
R 9Be selected from C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) nCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) nHeterocyclic radical ,-(CH 2) nAryl and-(CH 2) nHeteroaryl, CN;
The m representative is selected from following integer: 0,1,2,3,4 and 5;
The n representative is selected from following integer: 0,1,2,3,4 and 5;
The p representative is selected from following integer: 0 and 1;
The q representative is selected from following integer: 0,1 and 2;
The t representative is selected from following integer: 1 and 2;
The w representative is selected from following integer: 2,3 and 4;
Be used for the treatment of purposes in the medicine that the lipid metabolism obstacle comprises hyperlipemia or hyperlipoproteinemia in preparation.Especially; provide formula (II) compound to be used for the treatment of diabetes hyperlipemia or to mix hyperlipemia in preparation; in heart failure; hypercholesterolemia, 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 a specific embodiments of the present invention, provide formula (I) or (II) compound or its pharmaceutically acceptable derivates are used for the treatment of the lipid metabolism obstacle and comprise hyperlipemia or hyperlipoproteinemia.In another embodiment; provide formula (I) or (II) compound be used for the treatment of diabetes hyperlipemia or mix hyperlipemia in preparation; in heart failure; hypercholesterolemia, 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.
Therefore; formula (I) is provided on the other hand in the present invention or (II) compound or its pharmaceutically acceptable derivates are used for people's medicine or veterinary drug; comprise hyperlipemia or hyperlipoproteinemia for example diabetes hyperlipemia and mixing hyperlipemia especially for treatment lipid metabolism obstacle; in heart failure; hypercholesterolemia; 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.
Formula (I) is provided on the other hand in the present invention or (II) compound or its pharmaceutically acceptable derivates are used for preparation treatment lipid metabolism obstacle and comprise for example diabetes hyperlipemia and mix hyperlipemia of hyperlipemia or hyperlipoproteinemia; in heart failure; hypercholesterolemia; 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.
In another specific embodiments of the present invention, provide formula (I) or (II) compound or its pharmaceutically acceptable derivates are used for the treatment of inflammatory diseases or illness, the particularly sacroiliitis (rheumatoid arthritis for example in joint 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 the inflammation of transplant organ (for example rejection) and many organ diseases (systemic lupus erythematous for example, Sepsis), struvite 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 one embodiment, formula (I) or (II) compound or its pharmaceutically acceptable derivates is used for the treatment of or preventing inflammation, diabetes and the cardiovascular disorder or the illness that comprise atherosclerosis, arteriosclerosis, hypertriglyceridemia and mixing hyperlipemia.
Aspect other or another, the invention provides treatment human or animal patient by the not enough caused disease of HM74A receptor activation or benefit from the method for the disease that activates this receptor, described method comprises the formula (I) that delivers medicine to described human or animal patient's significant quantity or (II) compound or its pharmaceutically acceptable derivates.
In a specific embodiments; the invention provides treatment lipid metabolism obstacle and comprise hyperlipemia or hyperlipoproteinemia for example diabetes hyperlipemia and mixing hyperlipemia; in heart failure; hypercholesterolemia; 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 the formula (I) that delivers medicine to described human or animal patient's significant quantity or (II) compound or its pharmaceutically acceptable derivates.Find that equally also these compounds are favourable in the method for treatment coronary artery disease, thrombosis, stenocardia, chronic renal failure, peripheral vascular disease and apoplexy, described method comprises the formula (I) that delivers medicine to described human or animal patient's significant quantity or (II) compound or its pharmaceutically acceptable derivates.
In a formula (I) or a specific embodiments (II), R 1Be selected from hydrogen, C 1-10Alkyl and-(alkylidene group) m-X-(alkylidene group) n-Y.
In a formula (I) or a specific embodiments (II), X represents A or A1.In formula (I) or another specific embodiments (II), A is selected from heteroaryl, heterocyclic radical, and A1 is selected from CH 2-O-(CH 2) wN (R 5) C (O) O-CH for example 2O (CH 2) 2NHC (O) O-, CH 2-N (R 5) C (O) O-CH for example 2-NHC (O) O, CH 2-N (R 5) C (O)-for example CH 2-NHC (O)-, CH 2-(O) p-(CH 2) qC (O) NR 5-CH for example 2C (O) NCH 3-, CH 2-N (R 5) C (O) N (R 5The CH of)-for example 2-NHC (O) NCH 3-, CH 2-C (O) N ((CH 2) wOH)-for example CH 2-C (O) N ((CH 2) 2OH)-, CH 2-NR 5-S (O) 2-CH for example 2-NH-S (O) 2-, CH 2-S (O) 2NR 5-CH for example 2-S (O) 2NCH 3-and CH 2-C (O) O-.In formula (I) or another specific embodiments (II), X represents A, and A represents heteroaryl.In formula (I) or another specific embodiments (II), A represents nitrogenous heteroatomic heteroaryl, for example triazolyl, furazan base,  di azoly, tetrazyl, imidazolyl or pyrazolyl.
In formula (I) or another specific embodiments (II), X represents A, for example heteroaryl or heterocyclic radical, or direct key.
In a formula (I) or a specific embodiments (II), the Y representative is selected from the group of following optional replacement: aryl, for example phenyl or naphthyl, heteroaryl, for example pyridyl, thiazolyl, thienyl, benzofuryl or indyl, and O-aryl, for example O-phenyl.
In formula (I) or another specific embodiments (II), Y is selected from following group and replaces by one or more: OR 5For example OH or OCH 3, halogen is F or Cl for example, and aryl is phenyl for example, C 1-6Haloalkyl is CF for example 3Or CH 2CF 3, OCF 3, (R 8) pCN is CN for example, (CH 2) q-N (R 5)-S (O) 2R 8NHS (O) for example 2CH 3And S (O) 2R 9S (O) for example 2CH 3
In a formula (I) or a specific embodiments (II), when X represents A or A1, and A representation ring alkyl, cycloalkenyl group, aryl, heteroaryl or heterocyclic radical, and A1 representative-CH 2-O-(CH 2) wN (R 5) C (O) O-,-CH 2-N (R 5) C (O) O-,-CH 2-N (R 5) C (O)-,-CH 2-(O) p-(CH 2) qC (O) NR 5-,-CH 2-N (R 5) C (O) N (R 5)-or-CH 2-C (O) N ((CH 2) wOH)-time, Y representative ring then, for example when X represented  di azoly, tetrazyl or pyrazolyl, then Y represented phenyl, pyridyl or thienyl, m is selected from 3 and 4 integer, and n is selected from 0 and 1 integer, for example m be 4 and n be 0, or m be 3 and n be 1;
In a formula (I) or a specific embodiments (II), R 1Be selected from: hydrogen; And C 1-10Alkyl, it can be chosen wantonly by one or more following groups and replace: cycloalkyl, heterocyclic radical, aryl, heteroaryl, C 1-6Haloalkyl, halogen, cyano group ,-OR 4,-(CH 2) nCOR 5,-CO 2R 4,-OCOR 4,-(CH 2) nNR 5R 7With-(NH) mCONR 5R 7In formula (I) or another specific embodiments (II), R 1Be selected from: hydrogen; And C 1-10Alkyl, it can be chosen wantonly by one or more following groups and replace: halogen, cyano group ,-OR 4,-(CH 2) nCOR 4,-CO 2R 4,-OCOR 4,-(CH 2) nNR 5R 6With-(NH) mCONR 5R 6
In formula (I) or another specific embodiments (II), R 1Be selected from: hydrogen and optional by-C that OH replaced 1-6Alkyl, for example methyl, butyl or CH 2CH 2OH.
In a formula (I) or a specific embodiments (II), R 1Be selected from: hydrogen and C 1-6Alkyl, for example methyl or butyl.
In a formula (I) or a specific embodiments (II), R 2Be selected from: C 4-10Alkyl and C 2-10Alkenyl, its each can choose wantonly and replace by one or more following groups: cycloalkyl, heterocyclic radical, aryl, heteroaryl, C 1-6Haloalkyl, halogen, cyano group ,-OR 4,-(CH 2) nCOR 5,-CO 2R 4,-OCOR 4,-(CH 2) nNR 5R 6With-(NH) mCONR 5R 6In formula (I) or another specific embodiments (II), R 2Can represent C 4-10Alkyl, it can be chosen wantonly by one or more following groups and replace: cycloalkyl, heterocyclic radical, aryl, heteroaryl, C 1-6Haloalkyl, halogen, cyano group ,-OR 4,-(CH 2) nCOR 4,-CO 2R 4,-OCOR 4,-(CH 2) nNR 5R 6With-(NH) mCONR 5R 6In another embodiment, R 2Be selected from C 4-6Alkyl is butyl or amyl group for example.
In a formula (I) or a specific embodiments (II), R 2Represent C 1-10Alkyl, it can be chosen wantonly by one or more following groups and replace: cycloalkyl, heterocyclic radical, aryl, heteroaryl, C 1-6Haloalkyl, halogen ,-CN ,-OR 4,-(CH 2) nCOR 5,-C (O) OR 4,-OCOR 4,-(CH 2) nNR 5R 6With-(NH) pCONR 5R 6In formula (I) or another specific embodiments (II), R 2Be selected from C 3-6Alkyl is butyl or amyl group for example.
In a formula (I) or a specific embodiments (II), R 3Be selected from: fluoro C 1-6Alkyl.In formula (I) or another specific embodiments (II), R 3Be selected from: fluoro C 1-4Alkyl is CF for example 3, CHF 2Or CF 2CF 3
In a formula (I) or a specific embodiments (II), R 4Be selected from: hydrogen, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) nCycloalkyl ,-(CH 2) nHeterocyclic radical ,-(CH 2) nAryl and-(CH 2) nHeteroaryl.In formula (I) or another specific embodiments (II), R 4Be selected from: hydrogen and C 1-4Alkyl.
In a formula (I) or a specific embodiments (II), R 1Be selected from: hydrogen and optional by-C that OH replaced 1-6Alkyl, R 2Be selected from: C 4-6Alkyl, and R 3Be selected from: fluoro C 1-4Alkyl, condition are to work as R 1Represent methylidene and R 3Represent CF 3The time, R 2Can not be isobutyl-.
In a formula (I) or a specific embodiments (II), R 5Be hydrogen.
In a formula (I) or a specific embodiments (II), R 7Be selected from: hydrogen and C 1-4Alkyl.
In formula (I) or another specific embodiments (II), condition be when X be A1, A1 be-O-and Y are for by the ring of aryl or heteroaryl replacement the time, then m is selected from 3,4 and 5 integer.
In a formula (I) or a specific embodiments (II), R 1And R 2Be different.
It should be understood that any combination that the present invention includes these specific embodiments, and comprise above-mentioned formula (I) or (II) concrete substituent all combinations of compound.
Concrete The compounds of this invention comprises:
3-butyl-1-methyl-8-(trifluoromethyl)-3,7--dihydro-1H-purine-2, the 6-diketone,
1,3-dibutyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
3-butyl-1-methyl-8-(pentafluoroethyl group)-3,7-dihydro-1H-purine-2, the 6-diketone,
8-(difluoromethyl)-1-methyl-3-amyl group-3,7-dihydro-1H-purine-2, the 6-diketone,
3-amyl group-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
1-(2-hydroxyethyl)-3-amyl group-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
3-butyl-1-{3-[3-(phenyl methyl)-1,2,4- diazole-5-yl] propyl group }-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
4-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] butyric acid,
3-butyl-1-[4-(3-phenyl-1,2,4- diazole-5-yl) butyl]-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] valeric acid,
3-butyl-1-{4-[3-(2-fluorophenyl)-1,2,4- diazole-5-yl] butyl }-8-(trifluoromethyl)-3,7-dihydro-1 H-purine-2, the 6-diketone,
3-butyl-1-{4-[3-(4-fluorophenyl)-1,2,4- diazole-5-yl] butyl }-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2, the 6-diketone,
3-butyl-1-{4-[3-(2-pyridyl)-1,2,4- diazole-5-yl] butyl }-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-two-ketone,
3-butyl-8-(trifluoromethyl)-1-(3-{3-[(2,4,6-trifluorophenyl) methyl]-1,2,4- diazole-5-yl } propyl group)-3,7-dihydro-1H-purine-2,6 diketone,
1-methyl-3-amyl group-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-diketone.
For the amount that obtains the required HM74A conditioning agent of desirable biological effect depends on various factors certainly, the concrete clinical disease of mode of administration and recipient for example.In general, per daily dose can be 0.1mg-1g/kg, typically is 0.1-100mg/kg.Intravenous administration dosage can be 0.01mg-0.1g/kg for example, typically is 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 HM74A conditioning agent of 0.01 μ g-1g in the unitary dose.Therefore, can contain for example 0.01 μ g-0.1g in the injection ampoule, the unit dose formulations of oral administration for example can contain for example 0.1mg-1g in tablet or the capsule.When The compounds of this invention during, do not find/anticipate toxicological 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 can contain 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 with the powder of HM74A conditioning agent or particle is optional prepares with one or more ancillary component compactings or moulding.Compressed tablets can be by preparing for example optional the compacting with tackiness agent, lubricant, inert diluent and/or surfactant/dispersant blended powder or particle of the The compounds of this invention of unrestricted flow (free-flowing) form in suitable machine.Molded (Moulded) tablet can be by carrying out molded preparing with the wetting powder compound of inert liquid diluent in suitable machine.
Can contain conventional excipients in the tablet of oral administration and the capsule, tackiness agent for example is 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.
Can prepare the preparation of oral administration suitably, the sustained release/prolongation that obtains active compound discharges.
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 easily.Usually contain the 0.1-5%w/wHM74A 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 (cetostearylalcohol), 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 any 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 hyperlipemia medicine (for example statins, the special class (fibrates) of chlorine 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 hyperlipemia drug regimen with other type uses, as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statins) or the special class of chlorine 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 its pharmacy acceptable salt; the derivative of solvate or physiologic function is used for combination therapy (combinationtherapy) lipid metabolism obstacle in preparation and comprises hyperlipemia or hyperlipoproteinemia for example diabetes hyperlipemia and mixing hyperlipemia; in heart failure; hypercholesterolemia; 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 exist by the form of using pharmaceutical preparation easily, therefore contains aforesaid combination and optional pharmaceutically acceptable carrier or the pharmaceutical preparation of vehicle and has 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 those skilled in the art can understand at an easy rate.
Therefore, the present invention provides on the other hand and has contained the combination with other therapeutic activity agent of formula (I) compound or its pharmaceutically acceptable derivates.
The alleged combination in front can exist by the form of using pharmaceutical preparation easily, and the pharmaceutical preparation that therefore contains aforesaid combination and pharmaceutically acceptable thinner, vehicle or carrier has represented the present invention on the other hand.For example, the pharmaceutical preparation that comprises compound or its pharmaceutically acceptable derivates and one or more pharmaceutically acceptable thinners, vehicle or carrier.
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.
General purifying and analytical procedure:
Mass spectrum (MS) is that [(ES+ve obtains MH using electrospray positively ionized (positive ionization) effect +And M (NH 4) +Molion] or electrospray positively ionized (negative ionization) acts on, and [(ES-ve obtains (M-H) -Molion] write down on the Fisons VG Platform mass spectrograph of pattern.
1H NMR spectrum is used Bruker DPX 400MHz spectrometer record, uses the tetramethyl-silicomethane as external standard.
Biotage TMChromatography is meant that instrument (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 method 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 (5cmx10mm 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 quality.
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 (10cmx21.2mm i.d.) and is used 0.1%HCO 2The aqueous solution of H (A) and MeCN (0.5%HCO 2H) (B), adopt and to have the general condition of gradient elution that following gradient diagram of system is shown " x to y " and carry out purifying: 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 -1Gilson 233 fraction collectors are started by UV (254 nm).
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), with suitable gradient wash-out on Combiflash Optix 10.
The compounds of this invention and pharmaceutically acceptable derivative thereof can be according to hereinafter described method preparations, and this has constituted another aspect of the present invention.
Method A:
Be used to prepare wherein R according to of the present invention 1Be H or alkyl, wherein R 1And R 2The method of formula that can be identical or different (I) or formula (II) compound, described method comprises:
Figure A20058004435600331
I) pyrimidine dione forms
Ii) alkylating
Iii) nitrosylation
Iv) reduction
V) xanthine forms
Method B:
Be used to prepare wherein R according to of the present invention 1And R 2The method of formula that can be identical or different (I) or formula (II) compound, described method comprises:
I) at N3 position selective alkylation
Ii) in the alkylation of N1 position
The iii) formylation of C8
The iv) fluorination of carbonyl
V) palladium mediated deprotection
If desired or necessary words, as the final step in any one above-mentioned synthetic method, resulting formula (I) or formula (II) compound can be converted into the pharmacy acceptable salt form, perhaps vice versa, perhaps a kind of salt form is converted into another kind of pharmacy acceptable salt form.
Abbreviation
AcOH acetate
Br wide (NMR)
The CDI carbonyl dimidazoles
D doublet (NMR)
DBAD azo-2-carboxylic acid di-t-butyl ester
The DCM methylene dichloride
The DIPEA diisopropylethylamine
The DMSO methyl-sulphoxide
DMF N, dinethylformamide
The EtOAc ethyl acetate
EtOH ethanol
H hour
The IPA Virahol
M multiplet (NMR)
The directed automated preparation method (Mass directed autoprep) of MDAP quality
The MeCN acetonitrile
MeOH methyl alcohol
Min minute
The NCS N-chloro-succinimide
The PFPA PFPA
Q quartet (NMR)
The rt room temperature
The RT retention time
S unimodal (NMR)
The SPE solid-phase extraction column
T triplet (NMR)
The TFA trifluoroacetic acid
The TFAA trifluoroacetic anhydride
The THF tetrahydrofuran (THF)
The improved Eagle substratum of DMEM Dulbecco
HEPES 4-(2-hydroxyethyl) piperazine-1-ethyl sulfonic acid
LiHMDS hexamethyl dimethyl silanyl lithium amide
Utilize following non-limiting example that the present invention is carried out exemplary illustration:
Synthetic embodiment
Embodiment 1
3-butyl-1-methyl-8-(trifluoromethyl)-, 7-dihydro-1H-purine-2,6-diketone
With 5,6-diaminostilbene-butyl-3-methyl-2,4 (1H, 3H)-pyrimidine dione (European Journal ofMedicinal Chemistry (1990), 25 (8), 653-8) mixture heating up of the purple of (290mg) and TFAA (6ml) refluxed 1 hour, then vacuum concentration.The resistates that generates (7ml) is handled with 2N NaOH (aqueous solution), and mixture heating up was refluxed 30 minutes.After being cooled to envrionment temperature, it is 4 that mixture is acidified to about pH with 3MHCl (aqueous solution).Filter to collect this throw out, and the solution of water: EtOH (2: 1) then the solution of water: EtOH (1: 1) wash.With the beige solid vacuum-drying (100mg, 25%) that generates.NMR; δ H(400MHz, d 6-DMSO) 0.90 (t, 3H, J=7.5Hz), 1.25-1.36 (m, 2H), 1.59-1.69 (m, 2H), 3.25 (s, 3H), 3.97 (t, 2H, J=7Hz), at δ H15 do not observe NH; M/z 291.2[MH +].
Embodiment 2
1,3-dibutyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-diketone
With 5, the 6-diaminostilbene, 3-dibutyl-2,4 (1H, 3H)-pyrimidine dione (Joumal of MedicinalChemistry (1991), 34 (1), 466-9) mixture heating up of the purple of (207mg) and TFAA (4ml) refluxed 1 hour, then vacuum concentration.The resistates that generates (5ml) is handled with 2N NaOH (aqueous solution), and mixture heating up was refluxed 30 minutes.After being cooled to envrionment temperature, it is 4 that mixture is acidified to about pH with 3M HCl (aqueous solution).Filter and collect this throw out, and pass through water: the solution weight crystallization of EtOH (2: 1) comes purifying.Filbert/orange solids 50 ℃ of following vacuum-dryings 48 hours, is obtained the title compound (35mg, 13%) of beige solid form.δ H(400MHz, d 6-DMSO) 0.90 (t, 6H, J=7Hz), 1.26-1.34 (m, 4H), 1.48-1.68 (eclipsed m, 4H), 3.89 (t, 2H, J=7Hz), 3.97 (t, 2H, J=7Hz), at δ H15 do not observe NH; M/z 333.2[MH +].
Embodiment 3
3-butyl-1-methyl-8-(pentafluoroethyl group)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20058004435600361
With 5,6-diaminostilbene-butyl-3-methyl-2,4 (1H, 3H)-pyrimidine dione (European Journal ofMedicinal Chemistry (1990), 25 (8), 653-8) (300mg, 1.41mmol) and the mixture of PFPA (PFPA) purple (6ml) at 60 ℃ of down heating 1 hour, vacuum concentration then.The resistates that generates (7ml) is handled with 2N NaOH (aqueous solution), and mixture was heated 30 minutes down at 90 ℃.After being cooled to room temperature, it is 4 that mixture is acidified to about pH with 3M HCl (aqueous solution).Filter and collect this throw out, wash with water, and vacuum-drying, the loose shape solid of light green/brown title compound (163mg, 34%) obtained.δ H(400MHz, d 6-DMSO) 0.89 (t, 3H, J=7.5Hz), 1.24-1.35 (m, 2H), 1.60-1.69 (m, 2H), 3.25 (s, 3H), 3.98 (t, 2H, J=7Hz), at δ H15 do not observe NH; M/z 358.4[MNH 4 +].
Embodiment 4
8-(difluoromethyl)-1-methyl-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
Figure A20058004435600362
With 8-(difluoromethyl)-1-methyl-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, degasification under the vacuum of solution in gentleness of 6-diketone in anhydrous THF (3ml) and anhydrous DMSO (0.3ml), and feed nitrogen.This process is repeated twice.Add Pd (PPh 3) 4(74mg, 0.064mmol), and with mixture degasification is once again.(374uL 4.3mmol), and at room temperature stirred 4 hours to add morpholine.Mixture is distributed between 2M HCl (aqueous solution) and EtOAC.Separate organic layer, with the salt washing, dry (MgSO 4) and concentrate.Resistates is dissolved among the MeOH, and by amino-propyl group SPE post (5g), with MeOH, use the 5%AcOH/MeOH wash-out subsequently.Concentrate this product fraction, obtain the title compound (98mg, 80%) of pale solid.δ H(400MHz，d 6-DMSO)0.85(t，3H，J＝7Hz)，1.23-1.35(m，4H)，1.61-1.71(m，2H)，3.25(s，3H)，3.96(t，2H，J＝7.5Hz)，7.12(t，1H，J＝53Hz)，14.59(br.s，1H)；m/z?287.2[MH +]。
8-(difluoromethyl)-1-methyl-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20058004435600371
Under nitrogen atmosphere, with 1-methyl-2,6-dioxo-3-amyl group-7-(2-propylene-1-yl)-2,3,6, (133mg 0.44mmol) joins in the pre-dry flask 7-tetrahydrochysene-1H-purine-8-formaldehyde.Add anhydrous DCM (3ml), (161uL 0.87mmol), and adds EtOH (1, about 0.09mmol) at last to add Deoxofluor (two-(2-methoxy ethyl) amino sulfur trifluoride) subsequently.Mixture was at room temperature stirred 4 hours, then at saturated NaHCO 3Distribute between (aqueous solution) and the DCM.Separate organic layer, with the salt washing, dry (MgSO 4) and concentrate, obtain the title compound (145mg) of yellow oily.m/z327.4[MH +]。
1-methyl-2,6-dioxo-3-amyl group-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-8-formaldehyde
Figure A20058004435600372
Under-78 ℃, with time of 10 min to 1-methyl-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (1.05g, 3.8mmol) THF (15ml) solution in add hexamethyl dimethyl silanyl Lithium Azide (hexane solution of 1M, 4mL, 4mmol).With solution stirring 0.5 hour, add then DMF (0.5mL, 6.5mmol), and with solution-78 ℃ of following restir 0.5 hour, with time of 2 hours it is warmed to room temperature subsequently.Should react with the termination of 2N HCl solution, between EtOAc/ salt solution, separate then.(with DCM to 5: purifying 1 DCM/EtOAc gradient elution) obtains title compound (0.35g, 30%) through silica gel chromatography.m/z?305[MH +]。
1-methyl-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
To 3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (0.20g, 0.76mmol) and methyl iodide (0.5mL, 4.9mmol) DMF (5ml) solution in add salt of wormwood (0.4g, 2.9mmol), and with mixture 50 ℃ of down heating 3 hours, cooling also separates mixture between EtOAc/ salt solution.Separation of organic substances, dry (MgSO 4) and concentrate, generate required product (0.21g, 100%).m/z277[MH +]。
3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20058004435600382
To 7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (0.61g, 3.2mmol) and amyl iodide (0.64g, add in DMF 3.2mmol) (7ml) solution yellow soda ash (0.60g, 5.7mmol), and with mixture 50 ℃ of down heating 18 hours.Between EtOAc/ salt solution, separate after the cooling and with mixture.Separation of organic substances, dry (MgSO 4) and concentrate, generate crude product, (with DCM to 5: purifying 1 DCM/EtOAc gradient elution) obtains title compound (0.47g, 56%) through silica gel chromatography with it.m/z263[MH +]。
Embodiment 5
3-amyl group-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20058004435600383
With 6-amino-5-nitroso-group-1-amyl group-2,4 (1H, 3H)-pyrimidine dione (500mg, 2.21mmol), the mixture of 10%Pd/C (100mg) and EtOH (100ml) vigorous stirring 4 hours under nitrogen atmosphere.Mixture is filtered by Celite, and vacuum concentrated filtrate, obtain light green solid 5, and 6-diaminostilbene-amyl group-2,4 (1H, 3H)-mixture (2: 1) of pyrimidine dione (62mg) and unknown product.Add trifluoroacetic anhydride (5ml), and reflux 1 hour, vacuum concentration then.2M NaOH (aqueous solution) (1 5ml) is joined in the thick resistates, and in 100 ℃ of heating 30 minutes.After being cooled to room temperature, it is 5 that mixture is acidified to about pH with 2M HCl (aqueous solution).Filter and collect the precipitation that generates, and under heating, be dissolved among the MeOH then, and then by aminopropyl post (5g), with 2%AcOH/MeOH, 5%AcOH/MeOH, 10%AcOH/MeOH and 15%AcOH/MeOH wash-out.Concentrate this product fraction, obtain the title compound (52mg) of pale solid.NMR; (400MHz, d 6-DMSO) δ H0.85 (t, 3H, J=7Hz), 1.22-1.31 (m, 4H), 1.61-1.66 (quintet, 2H, J=7Hz), 3.89 (t, 2H, J=7Hz), 11.39 (s, 1H), 15.3 (br.s, 1H) .m/z 291.2[MH +].
Figure A20058004435600391
6-amino-5-nitroso-group-1-amyl group-2,4 (1H, 3H)-pyrimidine dione
Figure A20058004435600392
With 6-amino-1-amyl group-2,4 (1H, 3H)-pyrimidine dione (3.0g, 15.2mmol), the mixture of AcOH (6ml) and 6M HCl (aqueous solution) is cooled to 0 ℃, drips NaNO then 2(1.2g, water 16.7mmol) (4mL) solution is handled.Mixture was stirred 45 minutes, and add entry (approximately 200mL).The purple solid that filter to generate, water (approximately 200ml) is washed, and 60 ℃ of following high vacuum dry 18 hours.Obtain purple solid title compound (2.08g, 60%).m/z?227.3[MH +]。
6-amino-1-amyl group-2,4 (1H, 3H)-pyrimidine dione
Figure A20058004435600401
With 2-cyano group-N-[(amyl group amino) carbonyl] (17.9g 0.091mol), the mixture heating up to 85 of EtOH (70ml) and water (40ml) ℃, and drips 10%NaOH (aqueous solution) (10ml) to ethanamide then.Should react and stir 1 hour, and be cooled to room temperature subsequently, it is 6 that dilute with water, and use 2M HCl (aqueous solution) then is acidified to about pH.Cool off this mixture (ice bath), filter then, and the solid that generates is washed with water, then 40 ℃ of following vacuum-dryings.Obtain the title compound (11.0g, 61%) of white solid thus.m/z?198.2[MH +]。
2-cyano group-N-[(amyl group amino) carbonyl] ethanamide
Figure A20058004435600402
With the amyl group urea (16.4g, 0.13mol), cyanoacetic acid (11.8g, 0.14mol) and the mixture of diacetyl oxide (30ml) 80 ℃ of down heating 2 hours.Mixture is cooled to room temperature, and and Et 2O (approximately 100ml) stirred 1 hour.Mixture is cooled to 0 ℃ (ice bath), and solid collected by filtration, obtains the title compound (17.9g, 72%) of white solid.m/z?196.1[MH +]。
Embodiment 5 (b): 3-amyl group-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-diketone (another kind Method)
Figure A20058004435600403
To 6-amino-5-nitroso-group-1-amyl group-2,4 (1H, 3H)-pyrimidine dione 0.227g, 1mmol) add in the suspension in anhydrous methylene chloride (5ml) trifluoroacetic anhydride (0.35mL, 2.5mmol).The faint yellow suspension that generates is at room temperature stirred 40min, and then with solution for vacuum concentration.
Resistates is dissolved in the two  alkane (25ml), and added 10% palladium/carbon (0.5g) and hydrogenation 1 hour.Leach catalyzer, wash with two  alkane, and with the filtrate vacuum concentration.Still more remaining initiators are so repeat this step of hydrogenation.After 1.5 hours, leach this catalyzer again, wash with two  alkane, and with the filtrate vacuum concentration.
Resistates is dissolved in the tetrahydrofuran (THF) (10ml), and adds 2N NaOH (5ml).Solution was stirred 2 hours down at 60 ℃.Thick reaction mixture is diluted with ethyl acetate and water, and use 2N HCl acidifying then.Organic phase is washed dry (MgSO with salt 4), and concentrate in a vacuum, obtain the title compound (140mg, 48%) of orange solids.
LC/MS：m/z?291[MH] +，RT?3.00min
1H?NMR(DMSO-d 6)δH?0.85(3H，t，J＝7Hz)，1.28(4H，m)，1.64(2H，m)，3.88(2H，t，J＝7Hz)，11.22(1H，br?s).
Embodiment 6
1-(2-hydroxyethyl)-3-amyl group-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20058004435600411
With 6-amino-1-amyl group-3-[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl]-2,4 (1H, 3H)-AcOH (10ml) solution of pyrimidine dione (970mg) (8ml) handles with 6M HCl (aqueous solution), and adds water (3ml) solution of NaNO2 (247mg) then.After 15 minutes, mixture is distributed between water and EtOAC.Separate organic layer, and water layer is extracted with EtOAc (x7).The extraction liquid that merges is washed with salt, and dry (MgSO4) also concentrates, and obtains purple oily matter (446mg).The suspension of this oily matter in DCM (12ml) is handled by dripping TFAA (12mL).After 10 minutes, concentrate this mixture, obtain yellow/brown oily matter (798mg).Under nitrogen atmosphere, a part of oily mater (150mg) was reacted 2.5 hours in THF (15ml).Mixture is filtered by Celite, and by washing with THF.Concentrate this filtrate, and handle once, then vacuum concentration with TFAA (5ml).2MNaOH (aqueous solution) (4ml) is joined in the resistates, and mixture was heated 30 minutes down at 50 ℃.After the cooling, it is 5 that mixture is acidified to about pH, and product is extracted with EtOAC.Separate organic layer, with the salt washing, dry (MgSO4) also concentrates.The resistates that generates is passed through auotoprep hplc, obtain title compound (32mg, 17%).NMR；(400MHz，d6-DMSO)δH?0.85(t，3H，J＝7Hz)，1.23-1.36(m，4H)，1.62-1.70(m，2H)，3.52(t，2H，J＝6.5Hz)，3.97(m，4H)，15.5(br.S，1H).m/z335.3[MH+]。
Figure A20058004435600421
6-amino-1-amyl group-3-[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl]-2,4 (1H, 3H)-pyrimidine dione
Figure A20058004435600422
With 6-amino-1-amyl group-2,4 (1H, 3H)-pyrimidine dione (300mg, 1.5mmol), Cs 2CO 3(595mg, 1.8mmol), 2-(2-bromine oxethyl) tetrahydrochysene-2H-pyrans (276uL, 1.8mmol) and the mixture of dry DMF (5ml) 40 ℃ of down heating 18 hours.Mixture is distributed between water and EtOAC.Separate organic layer, with the salt washing, dry (MgSO 4) and concentrate, obtain filbert jelly (198mg, 40%).m/z?326.3[MH +]。
Embodiment 7 (a): 3-butyl-1-{3-[3-(phenyl methyl)-1,2,4- diazole-5-yl] propyl group }-8-(trifluoro Methyl)-3,7-dihydro-1H-purine-2,6-diketone
Embodiment 7 (b): 4-[3-butyl-2,6-dihydro generation-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1- Base] butyric acid
A) 3-butyl-1-{3-[3-(phenyl methyl)-1,2,4- diazole-5-yl] propyl group }-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20058004435600423
With 4-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] butyric acid (0.181g, 0.5mmol) and CDI (0.089g 0.55mmol) is dissolved in the anhydrous dimethyl formamide (6mL).Under nitrogen atmosphere, at room temperature with solution stirring after 3 hours, add the benzyl amidoxim (0.083g, 0.55mmol), and with solution 90 ℃ of heating 20 hours down, then 110 ℃ of heating 4 hours down.With this reaction mixture vacuum concentration, obtain yellow oil.It on Teledyne IscoCombiFlash  Companion , is used 40g RediSep silica column (with chloroform/ethanol 0-15% gradient elution) purifying.The fraction that vacuum-evaporation is suitable then by two  alkane lyophilizes, obtains the title compound (142mg, 59%) of white lyophily (lyophilate)
LC/MS：m/z?477[MH] +，RT?3.57?min
1H?NMR(CDCl 3)δ H.0.98(3H，t，J＝7Hz)，1.41(2H，m)，1.76(2H，m)，2.23(2H，m)，2.95(2H，t，J＝8Hz)，4.00(2H，s)，4.14(2H，t，J＝8Hz)，4.22(2H，t，J＝7Hz)，7.27(5H，s)
B) 4-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] butyric acid
Figure A20058004435600431
With anhydrous methylene chloride (50ml) join 4-(4-amino-3-butyl-5-nitroso-group-2,6-dioxo-3,6-dihydro-1 (2H)-pyrimidyl) ethyl butyrate (3.26g, 10mmol) in, add subsequently trifluoroacetic anhydride (3.53mL, 25mmol).Yellow solution is at room temperature stirred 15min under nitrogen atmosphere, then vacuum concentration.Resistates is dissolved in the two  alkane (150ml), and adds 10% palladium/carbon (0.5g), and hydrogenation 2 hours.Leach catalyzer, wash with two  alkane, and vacuum concentrated filtrate.
Resistates is dissolved in the tetrahydrofuran (THF) (100ml), and adds 2N NaOH (50ml).Solution was stirred 1.5 hours down at 60 ℃, cool off and dilute with ethyl acetate (100ml) and water (30mL).Organic phase water (2x30mL) is extracted.It is 4 that the aqueous extract that merges is acidified to pH with 2N HCl.Filter the solid that generates, and wash with water, obtain the title compound 2.17g (60%) of light beige solid.
LC/MS：m/z?363[MH] +，RT?2.84min
1H?NMR(DMSO-d 6)δ H?0.90(3H，t，J＝7Hz)，1.31(2H，m)，1.64(2H，m)，1.80(2H，m)，2.24(2H，t，J＝7Hz)，3.89(2H，t，J＝7Hz)，3.95(4H，m)，12.01，(1H，br?s)，15.36，(1H，br?s)
C) 4-(4-amino-3-butyl-5-nitroso-group-2,6-dioxo-3,6-dihydro-1 (2H)-pyrimidyl) ethyl butyrate
Figure A20058004435600441
With 4-(4-amino-3-butyl-2,6-dioxo-3,6 dihydro-1 (2H)-pyrimidyl) ethyl butyrate 8.5g, 29.8mmol) be dissolved in the mixture of Glacial acetic acid (45ml) and 6M hydrochloric acid (24mL).Solution is cooled to-1 ℃, and drips Sodium Nitrite (2.26g, water 32.7mmol) (20ml) solution.After adding is finished, remove ice bath, and purple solution was stirred 1 hour.With solution with water (140ml) dilution, the product of separating behind the several minutes is filtered, water (350ml altogether) is washed, and 50 ℃ of following vacuum-dryings, obtains shocking pink solid title compound (6.61g).After leaving standstill, isolate another batch product (0.53g), then mother liquor being turned to pH with the 2N sodium hydroxide alkali is 6, and is extracted in the ethyl acetate (2x250mL).Extraction liquid vacuum concentration with merging obtains the 3rd batch title compound (1.23g).Ultimate production 8.37g, 86%.
LC/MS：m/z?327[MH] +，RT?2.58min
D) 4-(4-amino-3-butyl-2,6-dioxo-3,6-dihydro-1 (2H)-pyrimidyl) ethyl butyrate
Figure A20058004435600442
Under nitrogen atmosphere, with 6-amino-1-butyl-2,4 (1H, 3H)-pyrimidine dione (5.9g, 32.2mmol) and cesium carbonate (11.54g 35.4mmol) joins in the anhydrous dimethyl formamide.(5.07mL 35.4mmol), and at room temperature stirred mixture 22 hours to add 4-bromo-butyric acid ethyl ester.Reaction mixture is diluted with ethyl acetate (350ml), and wash with saturated sodium chloride solution (2x50mL).The water that merges is stripped with ethyl acetate.The organic phase that merges is washed dry (MgSO with saturated sodium chloride solution 4), and concentrate in a vacuum.Crude product on Teledyne Isco CombiFlash  Companion , is used 80g RediSep silica column (with chloroform/ethanol 0-40% gradient elution) purifying.With suitable fraction vacuum-evaporation, obtain the title compound of yellow oily, it leaves standstill post crystallization (5.36g, 56%).
LC/MS：m/z?298[MH] +，RT?2.49min
Embodiment 8 (a): 3-butyl-1-[4-(3-phenyl-1,2,4- diazole-5-yl) butyl]-8-(fluoroform Base)-3,7-dihydro-1H-purine-2,6-diketone
Embodiment 8 (b): 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine -1-yl] valeric acid
A) 3-butyl-1-[4-(3-phenyl-1,2,4- diazole-5-yl) butyl]-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-diketone
With 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] methyl valerate (0.1 56g, 0.4mmol), the benzyl amidoxim (60mg, 0.44mmol), the EtOH solution of 2 1%NaOEt (0.22mL, 0.6mmol) and the mixture of anhydrous EtOH (1ml) under microwave at 140 ℃ of heating 10min down.Mixture is diluted with EtOAc (30ml), and water (20ml), 2NHCl (20ml) and salt solution (5mL) are washed.Dry organic layer (Na 2SO 4), and concentrate in a vacuum, obtain yellow oil, and, obtain the lyophilic title compound of paste (95mg, 50%) then by two  alkane lyophilizes.
LC/MS：m/z?476[MH] +，RT?3.73?min
1H?NMR(CDCl 3)δ H.?0.97(3H，t，J＝7Hz)，1.41(2H，m)，1.77(2H，m)，1.87(2H，m)，1.97(2H，m)，3.02(2H，t，J＝7Hz)，4.17(4H，m)，7.47(3H，m)，8.04(2H，m)
B) 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] valeric acid
Figure A20058004435600452
With 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] methyl valerate
Figure A20058004435600453
With anhydrous methylene chloride (70ml) join 4-(4-amino-3-butyl-5-nitroso-group-2,6-dioxo-3,6-dihydro-1 (2H)-pyrimidyl) methyl valerate (5.06g, 15.5mmol) in, add trifluoroacetic anhydride (22mL, 10 equivalents) subsequently.This yellow solution is at room temperature stirred 25min under nitrogen atmosphere, and vacuum concentration then.
Resistates is dissolved in the two  alkane (250ml), and joins in 10% palladium/carbon (0.85g), and hydrogenation 2.25 hours.Leach catalyzer, wash with two  alkane, and vacuum concentrated filtrate.Resistates is dissolved in the tetrahydrofuran (THF) (100ml), and adds 2N NaOH (15.5ml).Solution was at room temperature stirred 3.5 hours.The 2N NaOH that adds other 8ml, and with this reaction mixture 60 ℃ of down heating 1.5 hours.With this reaction mixture cooling, and be concentrated into small volume in a vacuum, and between ethyl acetate and water, distribute.With organic phase water (2x) and salt washing.Aqueous extract 2NHCL acidifying with merging is extracted in the ethyl acetate (5x40ml), and uses saturated NaHCO then 3(3x30ml) and salt solution (30mL) strip.It is 4.5 that the water that merges is acidified to pH with 2N HCl, and filters the solid that generates, and washes with water, obtains the 5-[3-butyl-2 of beige solid, 6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] valeric acid 2.19g (38%).
Through MgSO 4Dry organic phase, and be condensed into yellow jelly in a vacuum, it leaves standstill after fixing, obtains pink solid 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] methyl valerate (0.9g, 15%).
5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] data of valeric acid:
LC/MS：m/z?377[MH] +，RT?2.91min
1H?NMR(DMSO-d 6)δ H.0.90(3H，t，J＝7Hz)，1.30(2H，t，J＝7Hz)，1.45-1.68(6H，m)，2.24(2H，t，J＝7Hz)，3.89(2H，t，J＝7Hz)，3.97(2H，t，J＝7Hz)，12.00(1H，br?s)
5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] data of methyl valerate:
LC/MS：m/z?391[MH] +，RT?3.15?min.
1H?NMR(CDCl 3)δ H?0.95(3H，t，J＝7Hz)，1.27(2H，t，J＝7Hz)，1.38(2H，m)1.75(2H，m)，2.06(2H，s)，2.36(2H，t，J＝7Hz)，3.62(3H，s)，4.03(2H，br)，4.14(2H，m)
C) 4-(4-amino-3-butyl-5-nitroso-group-2,6-dioxo-3,6-dihydro-1 (2H)-pyrimidyl) methyl valerate
Figure A20058004435600471
According to being prepared with 4-(4-amino-3-butyl-5-nitroso-group-2,6-dioxo-3,6-dihydro-1 (2H)-pyrimidyl) the similar method of ethyl butyrate.
LC/MS：m/z?327[MH] +，RT?2.54?min
D) 5-(4-amino-3-butyl-2,6-dioxo-3,6-dihydro-1 (2H)-pyrimidyl) methyl valerate
According to being prepared with 4-(4-amino-3-butyl-2,6-dioxo-3,6-dihydro-1 (2H)-pyrimidyl) method that ethyl butyrate is identical.
LC/MS：m/z?298[MH] +，RT?2.47?min
Embodiment 9:3-butyl-1-{4-[3-(2-fluorophenyl)-1,2,4- diazole-5-yl] butyl }-8-(fluoroform Base)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20058004435600473
With 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] valeric acid (0.301g, 0.8mmol) and CDI (0.153g 0.94mmol) is dissolved in the anhydrous dimethyl formamide (10mL).With solution after at room temperature stirring 4 hours under the nitrogen atmosphere, add 2-fluorine benzyl amidoxim (0.135g, 0.88mmol), and with solution 85 ℃ of heating 19 hours down.With the reaction mixture vacuum concentration, and on 10g aminopropyl SPE (10g), come purifying with methanol-eluted fractions.Evaporate this meoh eluate, obtain oily matter, it is further passed through the MDAP purifying.Merge relevant fraction (fractions), and concentrate in a vacuum, resistates by two  alkane lyophilizes, is obtained white lyophilic title compound (0.037g, 9%).LC/MS：m/z?495[MH] +，RT?3.68min
1H?NMR(CDCl 3)δ? H.0.97(3H，t，J＝7Hz)，1.40(2H，m)，1.77(2H，m)，1.88(2H，m)，1.97(2H，m)，3.05(2H，t，J＝7Hz)，4.17(2H，q，J＝7Hz)，7.19-7.29(2H，m)7.45-7.48(1H，m)8.02，(1H，dt，J＝8?and?2Hz)
Embodiment 10:3-butyl-1-{4-[3-(4-fluorophenyl)-1,2,4- diazole-5-yl] butyl }-8-(fluoroform Base)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20058004435600481
With 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] valeric acid (0.301g, 0.8mmol) and CDI (0.153g 0.94mmol) is dissolved in the anhydrous dimethyl formamide (10mL).With solution after at room temperature stirring 4 hours under the nitrogen atmosphere, add 4-fluorine benzyl amidoxim (0-135g, 0.88mmol), and with solution 85 ℃ of heating 22 hours down.With the reaction mixture vacuum concentration, be dissolved in the ethyl acetate, and wash with salt solution (2x20ml) and 0.1N HCl.Dry organic phase (MgSO 4), and concentrate in a vacuum, obtain the required product of faint yellow oily, it is left standstill post crystallization.This material by two  alkane lyophilizes, is obtained the lyophilic title compound of paste (0.225g, 57%).
LC/MS：m/z?495[MH] +，RT?3.77min
1H?NMR(CDCl 3)δ H.?0.97(3H，t，J＝7Hz)，1.27(2H，m)，1.77(2H，m)，1.87(2H，m，)，1.97(2H，m)，3.02(2H，t，J＝7Hz)，4.17(4H，m，)，7.1?5(2H，m，J＝9Hz)，8.04(2H，m).
Embodiment 11:3-butyl-1-{4-[3-(2-pyridyl)-1,2,4- diazole-5-yl] butyl }-8-(fluoroform Base)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20058004435600482
With 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] valeric acid 0.15g, 0.4mmol) and CDI (0.078g 0.48mmol) is dissolved in the anhydrous dimethyl formamide (5mL).With solution after at room temperature stirring 1.5 hours under the nitrogen atmosphere, add the 2-pyridyl together with amidoxime (0.06g, 0.44mmol), and with solution 90 ℃ of heating 16.5 hours down.With the reaction mixture vacuum concentration, and by the MDAP purifying.The fraction that evaporation is relevant obtains tawny solid title compound (0.017g, 9%).
LC/MS：m/z?478[MH] +，RT?3.28?min
1H?NMR(CDCl 3)δ H?0.95(3H，t，J＝7Hz)，1.39(2H，m，J＝7Hz)，1.75(2H，m)，1.84(2H，m)，1.96(2H，m)，3.07(2H，t，J＝7Hz)，4.14(4H，m)，7.41(1H，m)7.84(1H，dt，J＝8?and?2Hz)，8.10(1H，d，J＝8Hz)，8.75(1H，d，J＝4Hz)
Embodiment 12:3-butyl-8-(trifluoromethyl)-1-(3-{3-[(2,4,6-trifluorophenyl) methyl]-1,2,4- Diazole-5-yl } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20058004435600491
With 4-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] butyric acid (0.181g, 0.5mmol) and CDI (0.089g 0.55mmol) is dissolved in the anhydrous dimethyl formamide (6mL).Solution after at room temperature stirring 3 hours under the nitrogen atmosphere, is added 2,4,6-trifluoro benzyl amidoxim (0.112g, 0.55mmol), and with solution 90 ℃ of heating 20 hours down, then 110 ℃ of heating 6 hours down.With the reaction mixture vacuum concentration is yellow oil.It on Teledyne IscoCombiFlash  Companion , is used 35g RediSep silica post (gradient elution: chloroform/ethanol 0-15%) carry out purifying.The fraction that vacuum-evaporation is suitable after two  alkane lyophilizes, obtains the title compound (0.122g, 46%) of white solid.
LC/MS：m/z?531[MH] +，RT?3.61min
1H?NMR(CDCl 3)δ? H.0.97(3H，t，J＝7Hz)，1.41(2H，m)，1.76(2H，m)，2.23(2H，m)，2.95(2H，t，J＝8Hz)，4.00(2H，s)，4.14(2H，t，J＝8Hz)，4.22(2H，t，J＝7Hz)，6.67(2H，t，J＝7Hz).
Embodiment 13:1-methyl-3-amyl group-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-diketone
A) 1-methyl-3-amyl group-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-diketone
Figure A20058004435600501
With 6-amino-3-methyl-5-nitroso-group-1-amyl group-2,4 (1H, 3H)-pyrimidine dione (0.042g, handle with trifluoroacetic anhydride (1ml), and at room temperature stir 10mins by 0.18mmol) anhydrous DCM (2ml) solution.This solution of vacuum concentration, and resistates is dissolved in 1, in the 4-two  alkane (15ml), and under nitrogen atmosphere, reacted 6 hours with 10%Pd/C (70mg) and trifluoroacetic anhydride (0.1ml).Mixture is filtered by Celite, and concentrated filtrate, red oil obtained.Add THF (2ml), add 2M NaOH (aqueous solution) solution subsequently.Mixture is heated 10 mins down at 50 ℃.After the cooling, mixture is distributed between 2M HCl (aqueous solution) and EtOAC.Separate organic layer, with the salt washing, dry (MgSO 4) and concentrate.Title product by the MDAP purifying, is obtained the title compound (10mg, 19%) of white solid.
LC/MS?m/z?305[MH +]，RT?3.2mins.
1H?NMR；(d 6-DMSO)δ H?0.92(3H，t，J＝7Hz)，1.38(4H，m)，1.80(2H，m)，3.51(3H，s)，4.17(2H，t，J＝8Hz)，13.5(1H，br?s).
B) 6-amino-3-methyl-5-nitroso-group-1-amyl group-2,4 (1H, 3H)-pyrimidine dione
Figure A20058004435600502
According to being prepared with 4-(4-amino-3-butyl-5-nitroso-group-2,6-dioxo-3,6--dihydro-1 (2H)-pyrimidyl) the similar method of ethyl butyrate.
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 (16)

1. be selected from least a chemical entity in formula (I) compound and the pharmaceutically acceptable derivates thereof,
Figure A2005800443560002C1
Wherein:
R 1Representative is selected from following group: hydrogen, C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl and-(alkylidene group) m-X-(alkylidene group) n-Y,
Wherein X represents A, A1, A2 or direct key;
A representative is selected from following group: cycloalkylidene, inferior cycloalkenyl group, aryl, heteroaryl, heterocyclic radical ,-CH 2-OC (O)-;
The A1 representative is selected from following group :-CH 2-O-(CH 2) qAryl-O-,-CH 2-O-(CH 2) wN (R 5) C (O) O-,-CH 2-N (R 5) C (O) O-,-CH 2-N (R 5) C (O)-,-CH 2-(O) p-(CH 2) qC (O) NR 5-,-CH 2-N (R 5) C (O) N (R 5)-,-CH 2-C (O) N ((CH 2) wOH)-,-CH 2-NR 5-S (O) 2-, CH 2-S (O) 2NR 5-,-CH 2-C (O) O-,-O-,-NR 5-,-S-;
A2 representative :-CH (OH)-;
When X was A, A1 or A2, Y representative was selected from following group: heteroaryl, heterocyclic radical, aryl, cycloalkyl, cycloalkenyl group ,-O (CH 2) n-aryl ,-C (O) O-aryl ,-CH (aryl) 2,-CH (heteroaryl) 2,-C 1-6Haloalkyl ,-C (O) R 4,-NR 5R 7,-C (O) NR 5R 7,-NR 5C (O) R 7,-NR 5C (O) OR 7,-C (O) (CH 2) qOR 4, halogen, cyano group ,-N (R 5) C (O) OR 7,-OC (O) NR 5R 6,-NR 5C (O) R 8,-OR 5,-OC (O) R 4
When X was A1, Y was selected from :-O (CH 2) n-aryl ,-the O-heteroaryl ,-OR 5,-OC (O) R 5,-NH-aryl ,-OC (O) NR 5R 6,
N is selected from 2,3,4 and 5 integer;
When X was A1, Y was-CF 3, or when X was A2, n was selected from 1,2,3,4 and 5 integer;
When X was direct key, the Y representative was selected from following group :-C (O) (CH 2) qOR 5,-C (O)-aryl ,-C (O)-heteroaryl ,-C (O)-heterocyclic radical ,-heteroaryl ,-heterocyclic radical ,-aryl ,-cycloalkyl ,-cycloalkenyl group ,-C 1-6Haloalkyl ,-halogen ,-cyano group, 3 or 4 the ring condense system ,-CH (aryl) 2,-CH (heteroaryl) 2,-OR 5,-NR 5R 7,-NCOOR 8,-(O) pC (O) NR 5R 6,-NR 5C (O) R 8,-OR 5,-(O) pC (O) R 4
When Y contained ring, this ring can be chosen wantonly by one or more following groups and replace: C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, halogen ,-NH2, (CH 2) q-NR 5R 7,-(CH 2) q-(O) p-(CH 2) q-N (R 5) C (O) OR 8,-(CH 2) q-N (R 5) C (O) R 8,-(CH 2) q-(O) p-(CH 2) q-C (O) NR 5R 6,-(CH 2) q-N (R 5) C (O) N (R 5) R 6,-(CH 2) q-C (O) N ((CH 2) mOH) R 5,-(CH 2) q-N (R 5)-S (O) 2R 8,-CH 2-S (O) 2N (R 5) R 6,-C 1-6Haloalkyl ,-OCF 3,-OCH (F) 2,-OCH 2F ,-COOR 5,-OR 5,-(R 8) pCN ,-S (O 2) R 9,-(CH 2) nHeteroaryl ,-(CH 2) nHeterocyclic radical ,-(CH 2) nCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) nAryl;
R 2Be selected from: hydrogen; Or C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl, its each can choose wantonly and replace by one or more following groups: C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, C 1-6Haloalkyl, halogen ,-CN ,-OR 4,-(CH 2) nCOR 4,-C (O) OR 4,-OCOR 4,-(CH 2) nNR 5R 6,-(NH) pCONR 5R 6,-OCONR 5R 7With-NHC (O) OR 7
R 3Be selected from: halogenated C 1-6Alkyl;
R 4Be selected from: hydrogen, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) nCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) nHeterocyclic radical ,-(CH 2) nAryl and-(CH 2) nHeteroaryl;
R 5And R 6Be selected from: hydrogen and C 1-4Alkyl;
R 7Be selected from: hydrogen, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) tCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) tHeterocyclic radical ,-(CH 2) tAryl and-(CH 2) tHeteroaryl;
R 8Be selected from C 1-4Alkyl;
R 9Be selected from C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) nCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) nHeterocyclic radical ,-(CH 2) nAryl and-(CH 2) nHeteroaryl, CN;
The m representative is selected from following integer: 0,1,2,3,4 and 5;
The n representative is selected from following integer: 0,1,2,3,4 and 5;
The p representative is selected from following integer: 0 and 1;
The q representative is selected from following integer: 0,1 and 2;
The t representative is selected from following integer: 1 and 2;
The w representative is selected from following integer: 2,3 and 4;
Condition is:
I) work as R 1Represent hydrogen or C 1-3During alkyl, R 2Be different from R 1
Ii) work as R 1Represent ethyl, and R 3Represent CF 3The time, R 2Not CH 2-CH=CH 2With
Iii) work as R 1Represent methylidene, and R 3Represent CF 3The time, R 2It or not isobutyl-.
2. according at least a chemical entity of claim 1, R wherein 1Be selected from: hydrogen, C 1-10Alkyl and-(alkylidene group) m-X-(alkylidene group) n-Y.
3. according at least a chemical entity of claim 1 or 2, wherein X represents A or direct key.
4. according at least a chemical entity of claim 1 or 2, R wherein 1Be selected from: hydrogen and C 1-6Alkyl.
5. according to each at least a chemical entity in the aforementioned claim, wherein R 2Be selected from: C 4-6Alkyl.
6. according to each at least a chemical entity in the aforementioned claim, wherein R 3Be selected from: fluoro C 1-6Alkyl.
7. according to each at least a chemical entity in the aforementioned claim, wherein R 3Represent CF 3
8. be used for people's medicine or veterinary drug according to each at least a chemical entity of aforementioned claim.
9. according to each at least a chemical entity among the claim 1-7, it is used for the treatment of the lipid metabolism obstacle and comprises hyperlipemia and hyperlipoproteinemia and/or inflammatory diseases or illness.
10. according to each at least a chemical entity among the claim 1-7, it is used for the treatment of diabetes hyperlipemia, mixes hyperlipemia, heart failure, hypercholesterolemia, cardiovascular disorder comprise 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.
11. at least a chemical entity in the formula of being selected from (I) compound and the pharmaceutically acceptable derivates thereof,
Figure A2005800443560004C1
Wherein:
R 1Representative is selected from following group: hydrogen, C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl and-(alkylidene group) m-X-(alkylidene group) n-Y,
Wherein X represents A, A1, A2 or direct key;
A representative is selected from following group: cycloalkylidene, inferior cycloalkenyl group, aryl, heteroaryl, heterocyclic radical ,-CH 2-OC (O)-;
The A1 representative is selected from following group :-CH 2-O-(CH 2) qAryl-O-,-CH 2-O-(CH 2) wN (R 5) C (O) O-,-CH 2-N (R 5) C (O) O-,-CH 2-N (R 5) C (O)-,-CH 2-(O) p-(CH 2) qC (O) NR 5-,-CH 2-N (R 5) C (O) N (R 5)-,-CH 2-C (O) N ((CH 2) wOH)-,-CH 2-NR 5-S (O) 2-, CH 2-S (O) 2NR 5-,-CH 2-C (O) O-,-O-,-NR 5-,-S-;
A2 representative :-CH (OH)-;
When X was A, A1 or A2, Y representative was selected from following group: heteroaryl, heterocyclic radical, aryl, cycloalkyl, cycloalkenyl group ,-O (CH 2) n-aryl ,-C (O) O-aryl ,-CH (aryl) 2,-CH (heteroaryl) 2,-C 1-6Haloalkyl ,-C (O) R 4,-NR 5R 7,-C (O) NR 5R 7,-NR 5C (O) R 7,-NR 5C (O) OR 7,-C (O) (CH 2) qOR 4, halogen, cyano group ,-N (R 5) C (O) OR 7,-OC (O) NR 5R 6,-NR 5C (O) R 8,-OR 5,-OC (O) R 4
When X was A1, Y was selected from :-O (CH 2) n-aryl ,-the O-heteroaryl ,-OR 5,-OC (O) R 5,-NH-aryl ,-OC (O) NR 5R 6,
N is selected from 2,3,4 and 5 integer;
When X was A1, Y was-CF 3, or when X was A2, n was selected from 1,2,3,4 and 5 integer;
When X was direct key, the Y representative was selected from following group :-C (O) (CH 2) qOR 5,-C (O)-aryl ,-C (O)-heteroaryl ,-C (O)-heterocyclic radical ,-heteroaryl ,-heterocyclic radical ,-aryl ,-cycloalkyl ,-cycloalkenyl group ,-C 1-6Haloalkyl ,-halogen ,-cyano group, 3 or 4 the ring condense system ,-CH (aryl) 2,-CH (heteroaryl) 2,-OR 5,-NR 5R 7,-NCOOR 8,-(O) pC (O) NR 5R 6,-NR 5C (O) R 8,-OR 5,-(O) pC (O) R 4
When Y contained ring, this ring can be chosen wantonly by one or more following groups and replace: C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, halogen ,-NH 2, (CH 2) q-NR 5R 7,-(CH 2) q-(O) p-(CH 2) q-N (R 5) C (O) OR 8,-(CH 2) q-N (R 5) C (O) R 8,-(CH 2) q-(O) p-(CH 2) q-C (O) NR 5R 6,-(CH 2) q-N (R 5) C (O) N (R 5) R 6,-(CH 2) q-C (O) N ((CH 2) mOH) R 5,-(CH 2) q-N (R 5)-S (O) 2R 8,-CH 2-S (O) 2N (R 5) R 6,-C 1-6Haloalkyl ,-OCF 3,-OCH (F) 2,-OCH 2F ,-COOR 5,-OR 5,-(R 8) pCN ,-S (O 2) R 9,-(CH 2) nHeteroaryl ,-(CH 2) nHeterocyclic radical ,-(CH 2) nCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) nAryl;
R 2Be selected from: hydrogen; Or C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl, its each can choose wantonly and replace by one or more following groups: C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, C 1-6Haloalkyl, halogen ,-CN ,-OR 4,-(CH 2) nCOR 4,-C (O) OR 4,-OCOR 4,-(CH 2) nNR 5R 6,-(NH) pCONR 5R 6,-OCONR 5R 7With-NHC (O) OR 7
R 3Be selected from: halogenated C 1-6Alkyl;
R 4Be selected from: hydrogen, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) nCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) nHeterocyclic radical ,-(CH 2) nAryl and-(CH 2) nHeteroaryl;
R 5And R 6Be selected from: hydrogen and C 1-4Alkyl;
R 7Be selected from: hydrogen, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) tCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) tHeterocyclic radical ,-(CH 2) tAryl and-(CH 2) tHeteroaryl;
R 8Be selected from C 1-4Alkyl;
R 9Be selected from C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) nCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) nHeterocyclic radical ,-(CH 2) nAryl and-(CH 2) nHeteroaryl, CN;
The m representative is selected from following integer: 0,1,2,3,4 and 5;
The n representative is selected from following integer: 0,1,2,3,4 and 5;
The p representative is selected from following integer: 0 and 1;
The q representative is selected from following integer: 0,1 and 2;
The t representative is selected from following integer: 1 and 2;
The w representative is selected from following integer: 2,3 and 4;
It is used for preparation treatment diabetes hyperlipemia, mixes hyperlipemia, heart failure, hypercholesterolemia, cardiovascular disorder comprise atherosclerosis, arteriosclerosis and hypertriglyceridemia, type ii diabetes, type i diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, stenocardia, the medicine of chronic renal failure or apoplexy.
12. treatment has by the not enough caused illness of HM74A receptor activation or benefits from the human or animal patient's of the illness that activates the HM74A acceptor method, described method comprises to the formula that is selected from (II) compound of described human or animal patient's effective dosage and at least a chemical entity in the pharmaceutically acceptable derivates thereof
Wherein
R 1Representative is selected from following group: hydrogen, C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl and-(alkylidene group) m-X-(alkylidene group) n-Y,
Wherein X represents A, A1, A2 or direct key;
A representative is selected from following group: cycloalkylidene, inferior cycloalkenyl group, aryl, heteroaryl, heterocyclic radical ,-CH 2-OC (O)-;
The A1 representative is selected from following group :-CH 2-O-(CH 2) qAryl-O-,-CH 2-O-(CH 2) wN (R 5) C (O) O-,-CH 2-N (R 5) C (O) O-,-CH 2-N (R 5) C (O)-,-CH 2-(O) p-(CH 2) qC (O) NR 5-,-CH 2-N (R 5) C (O) N (R 5)-,-CH 2-C (O) N ((CH 2) wOH)-,-CH 2-NR 5-S (O) 2-, CH 2-S (O) 2NR 5-,-CH 2-C (O) O-,-O-,-NR 5-,-S-;
A2 representative :-CH (OH)-;
When X was A, A1 or A2, Y representative was selected from following group: heteroaryl, heterocyclic radical, aryl, cycloalkyl, cycloalkenyl group ,-O (CH 2) n-aryl ,-C (O) O-aryl ,-CH (aryl) 2,-CH (heteroaryl) 2,-C 1-6Haloalkyl ,-C (O) R 4,-NR 5R 7,-C (O) NR 5R 7,-NR 5C (O) R 7,-NR 5C (O) OR 7,-C (O) (CH 2) qOR 4, halogen, cyano group ,-N (R 5) C (O) OR 7,-OC (O) NR 5R 6,-NR 5C (O) R 8,-OR 5,-OC (O) R 4
When X was A1, Y was selected from :-O (CH 2) n-aryl ,-the O-heteroaryl ,-OR 5,-OC (O) R 5,-NH-aryl ,-OC (O) NR 5R 6,
N is selected from 2,3,4 and 5 integer;
When X was A1, Y was-CF 3, or when X was A2, n was selected from 1,2,3,4 and 5 integer;
When X was direct key, the Y representative was selected from following group :-C (O) (CH 2) qOR 5,-C (O)-aryl ,-C (O)-heteroaryl ,-C (O)-heterocyclic radical ,-heteroaryl ,-heterocyclic radical ,-aryl ,-cycloalkyl ,-cycloalkenyl group ,-C 1-6Haloalkyl ,-halogen ,-cyano group, 3 or 4 the ring condense system ,-CH (aryl) 2,-CH (heteroaryl) 2,-OR 5,-NR 5R 7,-NCOOR 8,-(O) pC (O) NR 5R 6,-NR 5C (O) R 8,-OR 5,-(O) pC (O) R 4
When Y contained ring, this ring can be chosen wantonly by one or more following groups and replace: C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, halogen ,-NH 2, (CH 2) q-NR 5R 7,-(CH 2) q-(O) p-(CH 2) q-N (R 5) C (O) OR 8,-(CH 2) q-N (R 5) C (O) R 8,-(CH 2) q-(O) p-(CH 2) q-C (O) NR 5R 6,-(CH 2) q-N (R 5) C (O) N (R 5) R 6,-(CH 2) q-C (O) N ((CH 2) mOH) R 5,-(CH 2) q-N (R 5)-S (O) 2R 8,-CH 2-S (O) 2N (R 5) R 6,-C 1-6Haloalkyl ,-OCF 3,-OCH (F) 2,-OCH 2F ,-COOR 5,-OR 5,-(R 8) pCN ,-S (O 2) R 9,-(CH 2) nHeteroaryl ,-(CH 2) nHeterocyclic radical ,-(CH 2) nCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) nAryl;
R 2Be selected from: hydrogen; Or C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl, its each can choose wantonly and replace by one or more following groups: C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, C 1-6Haloalkyl, halogen ,-CN ,-OR 4,-(CH 2) nCOR 4,-C (O) OR 4,-OCOR 4,-(CH 2) nNR 5R 6,-(NH) pCONR 5R 6,-OCONR 5R 7With-NHC (O) OR 7
R 3Be selected from: halogenated C 1-6Alkyl;
R 4Be selected from: hydrogen, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) nCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) nHeterocyclic radical ,-(CH 2) nAryl and-(CH 2) nHeteroaryl;
R 5And R 6Be selected from: hydrogen and C 1-4Alkyl;
R 7Be selected from: hydrogen, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) tCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) tHeterocyclic radical ,-(CH 2) tAryl and-(CH 2) tHeteroaryl;
R 8Be selected from C 1-4Alkyl;
R 9Be selected from C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-(CH 2) nCycloalkyl ,-(CH 2) nCycloalkenyl group ,-(CH 2) nHeterocyclic radical ,-(CH 2) nAryl and-(CH 2) nHeteroaryl, CN;
The m representative is selected from following integer: 0,1,2,3,4 and 5;
The n representative is selected from following integer: 0,1,2,3,4 and 5;
The p representative is selected from following integer: 0 and 1;
The q representative is selected from following integer: 0,1 and 2;
The t representative is selected from following integer: 1 and 2;
The w representative is selected from following integer: 2,3 and 4.
13. according to the method for claim 12, wherein said human or animal patient suffers from the lipid metabolism obstacle and comprises hyperlipemia or hyperlipoproteinemia or inflammatory diseases or illness.
14. pharmaceutical preparation, it contains among the with good grounds claim 1-7 each at least a chemical entity and one or more pharmaceutically acceptable thinners, vehicle or carrier.
15. be used for together or separately, successively or the combination of administration simultaneously with alone or in combination pharmaceutical dosage forms, described combination comprises according to each at least a chemical entity and other therapeutic activity agent among the claim 1-7.
16. pharmaceutical preparation, it contains:
(i) according to each at least a chemical entity among the claim 1-7;
(ii) one or more are selected from the activeconstituents in statins, the special class of chlorine shellfish, bile acide binding resin and the nicotinic acid; And
(iii) one or more pharmaceutically acceptable thinners, vehicle or carrier.
CN 200580044356 2004-10-22 2005-10-20 Xanthine derivatives with hm74a receptor activity Pending CN101087790A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102245606A (en) * 2008-12-08 2011-11-16 葛兰素史密斯克莱有限责任公司 Novel compounds
CN114727983A (en) * 2019-09-25 2022-07-08 金翅雀生物公司 Xanthine CB1 inhibitors

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102245606A (en) * 2008-12-08 2011-11-16 葛兰素史密斯克莱有限责任公司 Novel compounds
CN102245606B (en) * 2008-12-08 2014-08-20 葛兰素史密斯克莱有限责任公司 Novel compounds
CN114727983A (en) * 2019-09-25 2022-07-08 金翅雀生物公司 Xanthine CB1 inhibitors

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