CN1980930A - 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and the use in the form of a DPP-IV inhibitor - Google Patents

8-[3-amino-piperidin-1-yl]-xanthines, their preparation and the use in the form of a DPP-IV inhibitor Download PDF

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Publication number
CN1980930A
CN1980930A CNA2005800054231A CN200580005423A CN1980930A CN 1980930 A CN1980930 A CN 1980930A CN A2005800054231 A CNA2005800054231 A CN A2005800054231A CN 200580005423 A CN200580005423 A CN 200580005423A CN 1980930 A CN1980930 A CN 1980930A
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Prior art keywords
methyl
benzyl
group
cyano group
xanthine
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CNA2005800054231A
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Chinese (zh)
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CN1980930B (en
Inventor
弗兰克·希梅尔斯巴赫
埃尔克·兰科普
马赛厄斯·埃克哈特
穆罕麦德·泰达扬
利奥·托马斯
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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Priority claimed from DE102004012921A external-priority patent/DE102004012921A1/en
Priority claimed from DE102004032263A external-priority patent/DE102004032263A1/en
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Priority claimed from PCT/EP2005/001427 external-priority patent/WO2005085246A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3

Abstract

The invention relates to substituted xanthines of general formula (I), wherein R is such as defined in claim 1, and to the tautomers, stereoisomers, mixtures and the salts thereof, said products exhibiting precious pharmacological properties, in particular an inhibiting effect on a dipeptidylpeptidasa-IV (DPP-IV) enzyme activity.

Description

8-[3-amino-piperadine-1-yl]-xanthine, the purposes of its preparation and DPP-IV inhibitor form
Technical field that the present invention belongs to
The invention relates to the xanthine of the replacement of following general formula, its tautomer, enantiomer, steric isomer, its mixture and salt thereof, particularly itself and mineral acid or the physiologically acceptable salt of organic acid,
It has the valuable pharmacological characteristic, particularly to inhibiting its preparation of the active tool of DPP IV (DPP-IV), its application on prevention or treatment and active relevant disease or the situation, particularly I type or type ii diabetes that maybe can be treated by reduction DPP-IV activity or alleviate of the DPP-IV that increases, the pharmaceutical composition of compound that contains general formula (I) or its physiologically acceptable salt and preparation method thereof.
Can learn from WO 02/068420, WO02/025 60, WO 03/004496, WO 03/024965, WO 04/018468, WO 04/048379, JP 2003300977 and EP 1338595 the xanthine derivative that DPP-IV is inhibited.
Summary of the invention
In following formula (I)
R represents benzyl, 2-luorobenzyl, 3-luorobenzyl, 4-luorobenzyl, 2,6-two fluoro-benzyls, 3, and 4-two fluoro-benzyls, 2-benzyl chloride base, 3-benzyl chloride base or 4-benzyl chloride base group,
2-trifluoromethyl-benzyl, 3-trifluoromethyl-benzyl or 4-trifluoromethyl-benzyl group,
3-trifluoromethoxy-benzyl or 4-trifluoromethoxy-benzyl group,
2-cyano group benzyl, 3-cyano group benzyl or 4-cyano group benzyl group,
2,6-dicyano benzyl, 3,4-dicyano benzyl, 3,5-dicyano benzyl, 2-trifluoromethyl-4-cyano group-benzyl, 3-nitro-4-cyano group-benzyl, 2-cyano group-3-methoxyl group-benzyl, 2-cyano group-4-methoxyl group-benzyl, 2-cyano group-5-methoxyl group-benzyl, 2-cyano group-4-fluoro-benzyl, 2-cyano group-5-fluoro-benzyl, 2-cyano group-6-fluoro-benzyl, 3-cyano group-4-fluoro-benzyl, 4-cyano group-3-fluoro-benzyl, 2-fluoro-4-cyano group-benzyl, 2-cyano group-3-benzyl chloride base, 2-chloro-4-cyano group-benzyl or 2-cyano group-4-bromobenzyl group
2-methoxyl group-benzyl, 3-methoxyl group-benzyl, 4-methoxyl group-benzyl, 2-fluoro-3-methoxyl group-benzyl, 2-fluoro-4-methoxyl group-benzyl, 2-fluoro-5-methoxyl group-benzyl, 3-fluoro-4-methoxyl group-benzyl, 3,4-dimethoxy-benzyl, 3,5-veratryl or 3,4-dimethoxy-6-fluoro-benzyl group
(benzo [1,3] dioxole-5-yl) methyl group,
[(4-cyano group-benzo [1,3] dioxole-5-yl) methyl group,
2-(3-encircles propoxy--phenyl)-2-oxo-ethyl, 2-(3-cyclo propyl methoxy-phenyl)-2-oxo-ethyl or 2-(3-cyclobutoxy group-phenyl)-2-oxo-ethyl group,
2-oxo-2-[2-(pyridin-3-yl)-phenyl]-ethyl or 2-oxo-2-[2-(pyridin-4-yl)-phenyl]-ethyl group,
(3-cyano group-naphthalene-1-yl) methyl, (1,4-dicyano-naphthalene-2-yl) methyl or (2,4-dimethoxy-naphthalene-1-yl) methyl group,
(furans-2-yl) methyl, (furans-3-yl) methyl, (5-bromo-furans-2-yl) methyl, (5-methyl-furans-2-yl) methyl, (5-cyano group-furans-2-yl) methyl or (5-methoxycarbonyl-furans-2-yl) methyl group,
(pyridine-2-yl) methyl, (6-fluoro-pyridine-2-yl) methyl or (5-methoxyl group-pyridine-2-yl) methyl group,
(3-cyanopyridine-2-yl) methyl, (6-cyanopyridine-2-yl) methyl, (5-cyano group-pyridine-2-yl) methyl, (4-cyano group-pyridine-2-yl) methyl, (4-cyano group-pyridin-3-yl) methyl, (3-cyano group-pyridin-4-yl) methyl, (2-cyano group-pyridin-3-yl) methyl, (2-cyano group-pyridin-4-yl) methyl, (5-cyano group-pyridin-3-yl) methyl, (6-cyano group-pyridin-3-yl) methyl or (5-cyano group-6-methoxyl group-pyridine-2-yl) methyl group
(6-phenyl-pyridine-2-yl) methyl or ([2,2 '] bipyridyl-6-yl) methyl group,
(pyrimidine-2-base) methyl, (4-methyl-pyrimidine-2-base) methyl or (4,6-dimethyl-pyrimidine-2-base) methyl group,
(2-phenyl-pyrimidine-4-yl) methyl or (4-phenyl-pyrimidine-2-yl) methyl group,
[(1-methyl isophthalic acid H-benzotriazole-5-yl) methyl] group,
(6-fluoro-quinoline-2-yl) methyl, (7-fluoro-quinoline-2-yl) methyl, (2-methyl-quinolyl-4) methyl, (3-cyano group-quinoline-2-yl) methyl, (3-cyano group-4-methyl-quinoline-2-yl) methyl, (4-cyano group-quinoline-2-yl) methyl, (5-cyano group-quinoline-2-yl) methyl, (8-cyano group-quinoline-2-yl) methyl, (6-amino-quinoline-2-yl) methyl, (8-amino-quinoline-2-yl) methyl, (4-methoxy yl-quinoline-2-yl) methyl, (6-methoxy yl-quinoline-2-yl) methyl, (6,7-dimethoxy yl-quinoline-2-yl) methyl or (8-cyano group-quinoline-7-yl) methyl group
(1-cyano group-isoquinoline 99.9-3-yl) methyl, (4-cyano group-isoquinolyl-1) methyl-(4-cyano group-isoquinoline 99.9-3-yl) methyl or [(4-(pyridine-2-yl)-isoquinolyl-1) methyl group,
(quinazoline-6-yl) methyl, (quinazoline-7-yl) methyl, (2-methyl-quinazoline-4-yl) methyl, (4,5-dimethyl-quinazoline-2-yl) methyl, (4-ethyl-quinazoline-2-yl) methyl, (4-cyclopropyl-quinazoline-2-yl) methyl, (2-phenyl-quinazoline-4-yl) methyl, (4-cyano group-quinazoline-2-yl) methyl, (4-phenyl amino-quinazoline-2-yl) methyl or (4-benzyl amino-quinazolines-2-yl) methyl group
(quinoxaline-5-yl) methyl-(quinoxalin-6-yl) methyl or (2,3-dimethyl-quinoxalin-6-yl) methyl group, or
([1,5] naphthyridine-3-yl) methyl group,
Its tautomer, enantiomer, diastereomer, its mixture and its salt.
Be preferably the compound of following general formula
The wherein definition in R such as the preamble, and tautomer and salt.
Also be preferably as follows the compound of general formula
The wherein definition in R such as the preamble, and tautomer and salt.
According to the present invention, the compound of general formula I is by itself known method acquisition, for example by following method:
A) with compound and 3-amino piperidine, its enantiomer or the reactant salt of following general formula
Wherein
Definition in R such as the preamble and
Z 1Represent a leavings group, for example: halogen atom, replacement hydroxyl, sulfydryl, sulfinyl, alkylsulfonyl or sulfonyloxy group, for example: chlorine or bromine atom, methylsulfonyl or mesyloxy group.
This reaction is at solvent such as Virahol easily, butanols, tetrahydrofuran (THF) diox, dimethyl formamide, dimethyl sulfoxide (DMSO), ethylene glycol monomethyl ether, ethylene glycol diethyl ether or tetramethylene sulfone (sulpholane), choose wantonly at inorganic or uncle's organic bases (tertiary organic base), for example: yellow soda ash, salt of wormwood or potassium hydroxide, uncle's organic bases, for example: triethylamine, or under the existence of N-ethyl-Diisopropylamine (Hunig alkali), carry out, yet these organic basess also can be simultaneously as solvent, and choose wantonly in the presence of reaction promotor such as alkali metal halide or palladium-based catalyst, under-20 to 180 ℃ temperature, but preferably under-10 to 120 ℃ temperature, carry out.Yet this reaction also can be solvent-free or carry out in excessive 3-amino piperidine.
B) compound with following general formula goes protection
The wherein definition in R such as the preamble.
Its tertbutyloxycarbonyl group is preferably by with acid as trifluoracetic acid or salt acid treatment or by with bromotrimethylsilane or Iodotrimethylsilane processing, optional solvent such as methylene dichloride, ethyl acetate, diox, methyl alcohol, Virahol or the ether of using, in addition cracking under 0 to 80 ℃ temperature.
In above-mentioned reaction, existing any reactive group, for example: amino, alkylamino or imino group can be protected by the blocking group of routine between the reaction period, and after reaction again with it removal.
For example; the blocking group of amino, alkylamino or imino group can be formyl radical, ethanoyl, fluoroform acyl group, ethoxycarbonyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), benzyl, methoxybenzyl or 2; 4-veratryl group and in addition, the phthaloyl group is applicable to amino.
Employed any blocking group is optional subsequently by for example: in aqueous solvent such as water, isopropanol, acetic acid/water, tetrahydrofuran (THF)/water Huo diox/water; acid as trifluoracetic acid, hydrochloric acid or sulfuric acid in the presence of in the presence of alkali metal base such as sodium hydroxide or potassium hydroxide or non-proton property as in the presence of Iodotrimethylsilane; at 0 to 120 ℃, be that preferably hydrolysis is removed under 10 to 100 ℃ the temperature.
Yet, benzyl, methoxybenzyl or carbobenzoxy-(Cbz) group be by hydrogenolysis for example as with hydrogen in the presence of catalyzer such as palladium/charcoal, in appropriate solvent such as methyl alcohol, ethanol, ethyl acetate or Glacial acetic acid, the sour example hydrochloric acid of optional interpolation, under 0-100 ℃ temperature, but preferred under 20 to 60 ℃ envrionment temperature, and be 1 to 7 crust in hydrogen pressure, remove but be preferably 3 to 5 crust.Yet, 2,4-veratryl group is preferable under the existence of methyl-phenoxide, removes in trifluoracetic acid.
The removal of tertbutyloxycarbonyl group is preferably handled optional use solvent such as methylene dichloride, diox, methyl alcohol or ether by acid as trifluoracetic acid or salt acid treatment or by Iodotrimethylsilane.
The trifluoroacetyl group group is preferably handled by sour example hydrochloric acid, chooses wantonly in the presence of solvent such as acetic acid, handles under 50 to 120 ℃ temperature or by sodium hydroxide solution, chooses wantonly in the presence of solvent such as tetrahydrofuran (THF), removes under 0 to 50 ℃ temperature.
The phthaloyl group preferably the hydrazine in solvent such as methyl alcohol, ethanol, Virahol, toluene or diox or primary amine such as methylamine, ethamine, thanomin or n-Butyl Amine 99 in the presence of, under 20 to 50 ℃ temperature, remove.
Moreover the compound of the general formula I of acquisition can resolve into its enantiomer and/or diastereomer, as mentioned before.Therefore, for example, suitable/back mixing compound can resolve into its cis and trans-isomer(ide), and the compound with at least one optical activity carbon atom is separable into its enantiomer.
Therefore, for example, obtained suitable/back mixing compound can be separated into its cis and trans-isomer(ide) by chromatography, the compound of the obtained general formula I that is raceme can be by known method (cf.Allinger N.L.and Eliel E.L.in " Topics in Stereochemistry " itself, Vol.6, WileyInterscience, 1971) be separated into its optics enantiomer and have the compound of the general formula I of at least 2 unsymmetrical carbons can be according to its physical-chemical difference, the known method of use itself, for example make it to become its diastereomer by chromatography and/or Steppecd crystallization, if and these compounds are to obtain with racemization type form, its can be subsequently as above-mentioned method make it to resolve into enantiomer.
The separation of enantiomer preferably separate by post according to palmistry or in the optically active solvent of tool recrystallization or by with the optically active substance that can form salt or derivative such as ester class or amides with racemoid, particularly acids and activatory derivative thereof or its alcohols reaction, and separation so the salt that obtains or the non-mirror image isomerism mixture of derivative, for example:, and the free enantiomorph is disengaged in pure diastereo-isomerism salt or derivative by the effect of suitable reagent according to the difference of its solubleness.Generally the optical activity acids of Shi Yonging for example is: the tartrate of D-and L-type or dibenzoyl tartaric acid, two-o-tolyl tartrate, oxysuccinic acid, amygdalic acid, camphorsulfonic acid, L-glutamic acid, aspartic acid or quininic acid.Optical activity alcohol for example can be: the optical activity carboxyl groups in (+) or (-)-menthol and the amides for example can be: (+)-or (-)-menthyl oxygen base carbonyl.
In addition, the compound of the formula I of gained can be converted to its salt, particularly with inorganic or organic acid it is changed into physiologically acceptable salt for medicinal use.The acids that can be used for these purposes comprises, for example: hydrochloric acid, Hydrogen bromide, sulfuric acid, methylsulfonic acid, phosphoric acid, fumaric acid, succsinic acid, lactic acid, citric acid, tartrate or toxilic acid.
Can learn maybe and can be prepared (referring to example I to XXV) by document as the compound of the general formula I I of initial compounds and III by the method for from document, learning.
Person as described above, the physiological property that has value according to the compound and the physiologically acceptable salt thereof of general formula I of the present invention is particularly to the restraining effect of DPP-IV ferment.
The biological characteristics investigation of these compounds is as follows:
These materials and corresponding salt thereof suppress the active ability of DPP-IV can be confirmed that this experiment is to originate as DPP IV with the extract of human colon's JEG-3 Caco-2 in experiment.Be published in Proc.Natl.Acad.Sci.Vol.90 according to people such as Reiher, pp.5757-5761 (1993), title carry out the differentiation of cell to express to bring out DPP-IV for the explanation in the article of " Increased expression of intestinal cell line Caco-2 ".By under 4 ℃, 35, the cell in (0.04 t.i.u. Trypsin inhibitor,Trasylol, 0.5%Nonidet-P40, pH 8.0 for 10mM Tris HCl, 0.15 M NaCl) obtains cell extract to 000g centrifugal 30 minutes (removal cell debris) from cracking in damping fluid.
Following the carrying out that DPP-IV measures:
Matrix solution (AFC with 50 μ l; AFC is acid amides-4-trifluoromethyl tonka bean camphor), final concentration 100 μ M place in the black micro plate.With micropipet add 20 μ l the mensuration damping fluid (final concentration 50mM Tris HCl pH 7.8,50 mM NaCl, 1%DMSO).Make the reaction beginning by the dissolved Caco-2 protein (final concentration is every hole 0.14 μ g protein) that adds 30 μ l.The substances typical case to be measured who is studied dilutes to add 20 μ l more in advance, and measures the corresponding again minimizing of volume of damping fluid.Reaction is to carry out under envrionment temperature, and the reaction times is 60 minutes.In Victor 1420Multilabel Counter, measure fluorescence again with the excitation wavelength of 405nm and the emission wavelength of 535nm.In the proteinic mixture of no Caco-2 (replacing its volume), record placebo value (corresponding to 0% activity), in having the mixture that adds any material, do not record control value (corresponding to 100% activity) to measure damping fluid.The tested effectiveness of substances is with IC 50Value representation is that the dosage that contains 11 test point/activity curve from each case calculates and gets.The gained result is as follows:
Compound (embodiment number) DPPIV inhibition IC 50[nM]
1 6
1(3) 6
1(4) 9
1(6) 2
1(7) 5
1(12) 2
1(21) 2
1(26) 2
1(30) 2
1(31) 3
1(38) 1
1(39) 2
The compound that is prepared according to the present invention, for example the compound of embodiment 1 (30) warp is with after the 10mg/kg oral administration rat, and the tool good tolerability is not because of recording toxic side effects.
Suppress the active ability of DPP-IV with regard to it and see it, be applicable to illness or the disease that the active inhibition of any DPP-IV of being subjected to is influenced according to compound and its corresponding pharmaceutically useful salt of general formula I of the present invention.Thereby expection compound according to the present invention is applicable to prevention or treatment disease or illness, for example: I type and type ii diabetes, preceding diabetes (pre-diabetes), the glucose tolerance that reduces or the variation of fasting plasma glucose, diabetic complication (for example: retinopathy, ephrosis becomes or DPN), metabolic acidosis or ketoacidosis, reactive hypoglycemia disease, insulin resistance, metabolism venereal disease syndrome, the dyslipidemia of various causes, sacroiliitis, arteriosclerosis and relative disease, obesity, the osteoporosis that allotransplantation and thyrocalcitonin cause.In addition, these materials are applicable to prevention B-cell degradation, for example: the apoptosis or the necrosis of pancreas B-cell.This material also is applicable to improvement or repairs size and the number that the pancreatic cell function also can additionally increase pancreas B-cell.In addition, with regard to its glucagon-like peptide, for example: the role of GLP-1 and GLP-2 and with DPP-IV suppress related, compound expection according to the present invention is applicable to reach, especially, calm or calm effect, and help mortality ratio and sickness rate after postoperative alienation state or hormone stress reaction maybe may reduce myocardial infarction.Moreover it is suitable for to treat the relevant illness that reaches by GLP-1 or GLP-2 mediation of any and above-mentioned effect.Can also can be used as diuretic(s) or hypotensive agent and suitable according to compound of the present invention with prevention and treatment acute renal failure.Also can be according to compound of the present invention in order to the inflammation illness of treatment respiratory tract.It also is suitable for prevention and treatment chronic inflammatory intestinal disease, for example: irritable bowel syndrome (IBS), Crohn ' s disease or colonic ulcer and pancreatitis.It is also expected gastrointestinal injury or the infringement that can be used for all kinds for example colitis and enteritis person can be taken place.In addition, expection DPP-IV inhibitor and therefore can be used for treating Infertility or improve human or mammiferous fecundity according to compound of the present invention is if particularly this fecundity is relevant with insulin resistance or polycystic ovary disease.On the other hand, these materials are suitable for influencing sperm motility and therefore are suitable for as the male contraceptive.In addition, this material is suitable for treating the growth hormone deficiency relevant with limited growth, and can reasonably be applied to the sign that all can use tethelin.Based on restraining effect, also be suitable for to treat various autoimmune disorderss, for example according to compound of the present invention to DPP-IV: rheumatic arthritis, multiple sclerosis, thyroiditis and Basedow ' s disease, or the like.Its also can in order to the treatment virus disease and also can, for example: in HIV infects, in benign prostate hyperplasia, gingivitis, produce in order to stimulate blood, also can be in order to treatment neurone defective and neurodegenerative disorders, for example: alzheimer's disease.Illustrated compound also can particularly invade and shift at modification property (modifying) tumour in order to the treatment tumour; Example herein is its property cancer of pancreas, rodent cancer or breast cancer at the bottom of treatment T-cell lymphoma, kemia, cell based.Other indications are: the local asphyxia of apoplexy, various causes, Parkinson's formula disease and migraine.In addition, further indication comprises: folliculus and epidermis Keratoderma excessively, body and mind dependency, depressibility and the neural psychotic disorder of the keratinocyte hyperplasia, psoriasis, encephalomyelitis, glomerulonephritis, lipodystrophy and all kinds that increase.
Also can be used in combination according to compound of the present invention with other active substances.The therapeutical agent that is suitable for these combinations comprises, for example: antidiabetic, for example: N1,N1-Dimethylbiguanide (metformin), sulfonylurea (for example: Glyburide (glibenclamid), tolbutamide (tolbutamide), glimepiride (glimepiride), nateglinide (nateglinide), repaglinide (repaglinide), thiazolidinediones (for example: rosiglitazone (rosiglitazone), pioglitazone (pioglitazone)), PPAR-gamma agonist (for example: GI 262570) and antagonist, PPAR-γ/alpha modulators (for example: KRP 297), PPAR-γ/α/δ conditioning agent, the AMPK activator, ACC1 and ACC2 inhibitor, the DGAT inhibitor, the SMT3 receptor stimulant, 11 β-HSD inhibitor, FGF19 agonist or plan are like thing, and the α-Pu Taotang glycosidase inhibitor (for example: acarbose, voglibose), other DPPIV inhibitor, α 2 antagonists, Regular Insulin and insulin analog, GLP-1 and GLP-1 analogue are (for example: Yi Ending-4 (exendin-4)) or dextrin (amylin).Also can be: the SGLT2 inhibitor with following combined, for example: T-1095 or KGT-1251 (869682), protein Tyrosine phosphatase 1 inhibitor, can influence the material of the glucose products degraded in the liver, for example: G-6-Pase or fructose-1, the 6-bisphosphatase, the inhibitor of glycogen Phosphation enzyme, glucagon receptor antagonist and phosphoric acid enol pyruvic acid carboxylase, the inhibitor of glycogen synthetic enzyme or pyruvic dehydrogenase kinase, lipid lowering agent, for example: the HMG-CpA-reductase inhibitor (for example: Simvastatin (simvastatin), Zarator (atorvastatin)), the special class (fibrates) of shellfish (for example: bezafibrate (bezafibrate), Fen Ruobeite (fenofibeate)), niacin and derivatives class thereof, the PPAR-alfa agonists, the PPAR-delta agonists, the ACAT inhibitor (for example: avasimibe (avasimibe)) or cholesterol absorption inhibitor, for example: ezetimibe (ezetimibe), cholic acid associativity material, for example: Colestyramine (cholestyramine), ileum (ileac) cholic acid transmits inhibitor, the high density lipoprotein increasing compound, for example: the conditioning agent of CETP inhibitor or ABC1 or LXR alpha-2 antagonists, LXRbeta agonist or LXR α/β conditioning agent or the effective material of treatment of obesity, for example: sibutramine (sibutramine) or tetrahydrolipostatin, dexfenfluramine (dexfenfluramine), Dapiclermin (axokine), hemp 1 receptor antagonist, the MCH-1 receptor antagonist, the MC4 receptor stimulant, NPY5 or NPY2 antagonist or β 3-agonist, for example: the agonist of SB-418790 or AD-9677 and 5HT2c acceptor.
Also can be with this compound and the hypertensive medicine of treatment for example AII antagonist or ACE inhibitor, diuretic(s), beta blocker, Ca-antagonist, or the like, or its combination is combined.
Can be easily reaching the required dosage of these effects by intravenous route is 1 to 100mg, is preferably 1 to 30mg, and by oral route is 1 to 1000mg, is preferably 1 to 100mg, and each individuality is every day 1-4 time.At this purpose, formula I compound prepared in accordance with the present invention, optional combined with other active compounds, can and use with one or more conventional inert supports and/or thinner, for example: with W-Gum, lactose, glucose, Microcrystalline Cellulose, Magnesium Stearate, polyvidone, citric acid, tartrate, water, water/ethanol, water/glycerine, water/sorbyl alcohol, water/polyoxyethylene glycol, propylene glycol, cetostearyl alcohol (cetylstearyl alcohol), Cellulose,ether with glycolic acid or fatty substance, for example: stearic (hard fat) or its suitable mixture, and become traditional galenic preparation, for example: original shape or coated tablet, capsule, powder, suspension or suppository.
Embodiment
Following example is in order to explanation the present invention:
The preparation of initial compounds:
Example I
1-[(4-phenyl amino-quinazoline-2-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
3-methyl-7-(2-butyne-1-yl)-8-[3-(t-butoxycarbonyl amino)-piperidines-1-yl with 416mg]-xanthine and 456mg cesium carbonate be at the N of 4ml, stirred 10 minutes down in 80 ℃ in the mixture in the dinethylformamide, 2-chloromethyl-4-phenyl amino-the quinazoline that adds 324mg again, and this reaction mixture stirred two hours down in 80 ℃.Add other 50mg cesium carbonate and 50mg chloromethyl-4-phenyl amino-quinazoline then, and with this mixture in 80 ℃ of restir 1.5 hours.Again the solvent distillation is removed, and residue is distributed between water and ethyl acetate.With rare citric acid, water and saturated nacl aqueous solution washing organic phase, through dried over mgso and evaporation.By chromatography through silicagel column, with ethyl acetate/petroleum ether (8: 2 to 10: 0) as elutriant with the crude product purifying.
Output: 425mg (theoretical 65%)
R fValue: 0.33 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=650[M+H] +
Following compounds obtain similar embodiment I:
(1) methyl 1-[(4-benzyl amino-quinazolines-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.20 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=664[M+H] +
(2) methyl 1-[(2-methyl-quinolyl-4)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.80 (silica gel, methylene chloride=9: 1)
Mass spectrum (ESI +): m/z=572[M+H] +
(3) methyl 1-[(3-cyano group-naphthalene-1-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.67 (silica gel, methylene chloride=95: 5)
Mass spectrum (ESI +): m/z=582[M+H] +
(4) methyl 1-[(2-phenyl-quinazoline-4-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.75 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=635[M+H] +
(5) methyl 1-[(4-cyano group-isoquinolyl-1)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.75 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=583[M+H] +
(6) methyl 1-[(4-cyano group-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=583[M+H] +
(7) 1-[2-(3-encircles propoxy--phenyl)-2-oxygen base-ethyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.75 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=591[M+H] +
(8) 1-[2-(3-cyclo propyl methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.65 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=605[M+H] +
(9) 1-[2-(3-cyclobutoxy group-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.85 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=605[M+H] +
(10) methyl 1-[(1-cyano group-isoquinoline 99.9-3-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=583[M+H] +
(11) 1-[(2,4-methoxyl group-naphthalene-1-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.70 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=617[M+H] +
(12) 1-[(2,3-dimethyl-quinoxalin-6-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.50 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=587[M+H] +
(13) methyl 1-[(6-nitro-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.45 (silica gel, ethyl acetate/petroleum ether=7: 3)
Mass spectrum (ESI +): m/z=603[M+H] +
(14) methyl 1-[(quinoxaline-5-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=559[M+H] +
(15) methyl 1-[(6-methoxy yl-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.65 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=588[M+H] +
(16) methyl 1-[(6-phenyl-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.43 (silica gel, methylene chloride=96: 4)
Mass spectrum (ESI +): m/z=584[M+H] +
(17) 1-{[(4-(pyridine-2-yl)-isoquinolyl-1] methyl }-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
(18) methyl 1-[(7-fluoro-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.24 (silica gel, ethyl acetate/petroleum ether=1: 1)
Mass spectrum (ESI +): m/z=576[M+H] +
(19) methyl 1-[(8-nitro-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.63 (silica gel, methylene chloride=95: 5)
Mass spectrum (ESI +): m/z=603[M+H] +
(20) methyl 1-[(6-fluoro-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.47 (silica gel, methylene chloride=95: 5)
Mass spectrum (ESI +): m/z=576[M+H] +
(21) 1-[2-oxo-2-(2-bromo-phenyl)-ethyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.75 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=613,615[M+H] +
(22) 1-cyanogen methyl-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.80 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=456[M+H] +
(23) methyl 1-[(4-methoxy yl-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=588[M+H] +
(24) methyl 1-[(2-phenyl-pyrimidine-4-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.39 (silica gel, methylene chloride=96: 4)
Mass spectrum (ESI +): m/z=585[M+H] +
(25) 1-[([1,5] naphthyridine-3-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.28 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=559[M+H] +
(26) methyl 1-[(3-cyano group-4-methyl-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.75 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=597[M+H] +
(27) 1-[(4,5-dimethyl-quinazoline-2-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=587[M+H] +
(28) methyl 1-[(5-cyano group-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.42 (silica gel, petrol ether/ethyl acetate=1: 2)
Mass spectrum (ESI +): m/z=5 83[M+H] +
(29) methyl 1-[(3-cyano group-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.80 (silica gel, dichloromethane/ethyl acetate=1: 1)
(30) methyl 1-[(4-phenyl-pyrimidine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.46 (silica gel, ethyl acetate)
(31) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.75 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=580[M+H] +
(32) 1-[(1,4-dicyano-naphthalene-2-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.54 (silica gel, methylene chloride=95: 5)
Mass spectrum (ESI +): m/z=607[M+H] +
(33) 1-[(6,7-dimethoxy yl-quinoline-2-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.36 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=618[M+H] +
(34) methyl 1-[(quinazoline-6-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.20 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=559[M+H] +
(35) methyl 1-[(4-cyano group-quinazoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.40 (silica gel, dichloromethane/ethyl acetate=7: 3)
Mass spectrum (ESI +): m/z=584[M+H] +
(36) methyl 1-[quinazoline-7-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.20 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=559[M+H] +
(37) 1-(2-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.50 (silica gel, dichloromethane/ethyl acetate=7: 3)
Mass spectrum (ESI +): m/z=532[M+H] +
(38) 1-(3-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.58 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=532[M+H] +
(39) 1-(4-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.61 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=532[M+H] +
(40) methyl 1-[(pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=508[M+H] +
(41) 1-benzyl-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.70 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=507[M+H] +
(42) 1-(4-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.75 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=537[M+H] +
(43) 1-(2-chloro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.80 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=541,543[M+H] +
(44) 1-(2,6-dicyano-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=557[M+H] +
(45) 1-(2-cyano group-4-bromo-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=610,612[M+H] +
(46) 1-(3-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.80 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=525[M+H] +
(47) 1-(3,5-dimethoxy-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.70 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=567[M+H] +
(48) 1-(2-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.85 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=525[M+H] +
(49) methyl 1-[(6-cyano group-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.60 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=533[M+H] +
(50) methyl 1-[(3-cyano group-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.60 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=533[M+H] +
(51) 1-(2-cyano group-3-chloro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=566,568[M+H] +
(52) 1-(4-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.80 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=525[M+H] +
(53) 1-(4-chloro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.80 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=514,543[M+H] +
(54) 1-(2-cyano group-4-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=550[M+H] +
(55) 1-(3-cyano group-4-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=550[M+H] +
(56) 1-(2-chloro-4-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=566,568[M+H] +
(57) methyl 1-[(5-methoxycarbonyl-furans-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=555[M+H] +
(58) 1-(2-trifluoromethyl-4-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=600[M+H] +
(59) 1-(3,5-dicyano-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=557[M+H] +
(60) 1-(3-nitro-4-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=577[M+H] +
(61) methyl 1-[(2-cyano group-pyridin-3-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.50 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=533[M+H] +
(62) 1-(2-cyano group-4-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.70 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=562[M+H] +
(63) 1-(2-cyano group-5-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.75 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=562[M+H] +
(64) 1-(3-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.80 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=537[M+H] +
(65) 1-(3-trifluoromethyl-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.80 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=575[M+H] +
(66) 1-(3,4-dimethoxy-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.65 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=567[M+H] +
(67) 1-(3-chloro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.80 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=541,543[M+H] +
(68) 1-(4-trifluoromethyl-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.85 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=575[M+H] +
(69) 1-[([2,2 '] bipyridyl-6-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.53 (aluminum oxide, methylene chloride=98: 2)
Mass spectrum (ESI +): m/z=585[M+H] +
(70) 1-(3,4-dimethoxy-6-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.65 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=585[M+H] +
(71) methyl 1-[(6-fluoro-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=526[M+H] +
(72) methyl 1-[(5-cyano group-6-methoxyl group-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=5 63[M+H] +
(73) 1-(2,6-two fluoro-benzyls)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.62 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=543[M+H] +
(74) 1-(3-trifluoromethoxy-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.67 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=591[M+H] +
(75) 1-(4-trifluoromethoxy-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.62 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=591[M+H] +
(76) methyl 1-[(2-cyano group-pyridin-4-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.55 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=533[M+H] +
(77) methyl 1-[(5-cyano group-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.55 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=533[M+H] +
(78) methyl 1-[(pyrimidine-2-base)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.60 (silica gel, ethyl acetate/methanol=9: 1)
Mass spectrum (ESI +): m/z=5 09[M+H] +
(79) methyl 1-[(4-methyl-pyrimidine-2-base)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.60 (silica gel, ethyl acetate/methanol=9: 1)
Mass spectrum (ESI +): m/z=523[M+H] +
(80) 1-[(4,6-dimethyl-pyrimidine-2-base) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.70 (silica gel, ethyl acetate/methanol=9: 1)
Mass spectrum (ESI +): m/z=537[M+H] +
(81) methyl 1-[(quinoxalin-6-yl)]-3-methyl-7-(2-butyne-1-yl)-8-bromo-xanthine
R fValue: 0.55 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=439,441[M+H] +
(82) 1-(3-fluoro-4-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.70 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=555[M+H] +
(83) 1-(3,4-two fluoro-benzyls)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.75 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=543[M+H] +
(84) 1-(2-fluoro-5-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.55 (silica gel, ethyl acetate/petroleum ether=3: 2)
Mass spectrum (ESI +): m/z=555[M+H] +
(85) 1-(2-fluoro-3-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.48 (silica gel, ethyl acetate/petroleum ether=3: 2)
Mass spectrum (ESI +): m/z=555[M+H] +
(86) methyl 1-[(4-cyano group-isoquinoline 99.9-3-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.55 (silica gel, methylene chloride=95: 5)
Mass spectrum (ESI +): m/z=5 83[M+H] +
(87) 1-(2-fluoro-4-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.48 (silica gel, ethyl acetate/petroleum ether=1: 1)
Mass spectrum (ESI +): m/z=555[M+H] +
(88) methyl 1-[(furans-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=497[M+H] +
(89) 1-(3,4-dicyano-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=557[M+H] +
(90) 1-(4-cyano group-2-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=550[M+H] +
(91) (1-(2-cyano group-5-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=550[M+H] +
(92) methyl 1-[(5-formyl radical-furans-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=525[M+H] +
(93) 1-(2-cyano group-6-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
(94) 1-(4-cyano group-3-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=550[M+H] +
(95) 1-(2-cyano group-3-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-bromo-xanthine
R fValue: 0.85 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=442,444[M+H] +
(96) methyl 1-[(8-cyano group-quinoline-7-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.70 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=583[M+H] +
(97) methyl 1-[(4-cyano group-pyridin-3-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.40 (silica gel, ethyl acetate/hexanaphthene=3: 1)
Mass spectrum (ESI +): m/z=533[M+H] +
(98) methyl 1-[(8-cyano group-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.40 (silica gel, ethyl acetate/petroleum ether=4: 1)
Mass spectrum (ESI +): m/z=583[M+H] +
(99) methyl 1-[(1-methyl isophthalic acid H-benzotriazole-5-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.30 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=5 62[M+H] +
(100) methyl 1-[(3-cyano group-pyridin-4-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.30 (silica gel, dichloromethane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=533[M+H] +
(101) methyl 1-[(3-cyano group-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-bromo-xanthine
Mass spectrum (ESI +): m/z=413,415[M+H] +
(102) methyl 1-[(4-cyano group-benzo [1,3] dioxole-5-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.80 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=576[M+H] +
Example II
3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
(R)-3-t-butoxycarbonyl amino-piperidines of 11.00g is added in the 100ml dimethyl sulfoxide (DMSO) of 3-methyl-7-(2-butyne-1-the yl)-8-bromo-xanthine of 15.00g and 16.00g salt of wormwood and with should dense thick light beige suspension with mechanical stirrer in about 114 ℃ of stirrings 4 hours down.(the R)-3-t-butoxycarbonyl amino-piperidines that in this reaction mixture, adds the other 900mg be dissolved in the 10ml dimethyl sulfoxide (DMSO), and with it in 114 ℃ of following restir 2 hours.Be cooled to after the envrionment temperature, this reaction mixture is fully diluted with water.Thoroughly development is residual and with it filtration of bleeding until no block with the throw out that generated.Should suspend once more by the light color solid with water, suction filtration is washed and in addition dry with 60 ℃ in the drying by circulating air device with water and ether.
Output: 19.73g (theoretical 94%)
R fValue: 0.64 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=417[M+H] +
The acquisition and the example II of following compounds are similar:
(1) 3-methyl-7-(2-butyne-1-yl)-8-[(3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Fusing point: 235-237 ℃
Mass spectrum (ESI +): m/z=417[M+H] +
(2) methyl 1-[(quinoxalin-6-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.40 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=559[M+H] +
(3) methyl 1-[(5-methyl-furans-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=511[M+H] +
(4) 1-(2-cyano group-3-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.50 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=562[M+H] +
(5) methyl 1-[(3-cyano group-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(S)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.50 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=533[M+H] +
EXAMPLE III
3-methyl-7-(2-butyne-1-yl)-8-bromo-xanthine
The 1-bromo-2-butyne of 17.06g is added to the N of the 370ml of the 3-methyl-8-bromo-xanthine of 30.17g and 27.00mlH ü nig alkali, in the dinethylformamide.Under envrionment temperature, reaction mixture was stirred two hours, add the 1-bromo-2-butyne of other 1ml again and with reaction mixture restir 1 hour under envrionment temperature.In the subsequent disposal, reaction mixture is diluted with about 300ml water.With the light throw out that generated in addition suction filtration and with water washing it.With small amount of ethanol and ether washing leaching cake and in addition dry with 60 ℃ in the drying by circulating air machine.
Output: 30.50g (theoretical 84%)
R fValue: 0.24 (silica gel, methylene chloride=95: 5)
Mass spectrum (ESI +): m/z=297,299[M+H] +
EXAMPLE IV
2-chloromethyl-4-phenyl amino-quinazoline
By under envrionment temperature, the 12ml dichloromethane solution of the 4-chloro-2-chloromethyl-quinazoline of 500mg and 438mg aniline is reacted prepared.
Output: 518mg (theoretical 82%)
R fValue: 0.60 (silica gel, cyclohexane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=270,272[M+H] +
The acquisition of following compounds is similar embodiment IV:
(1) 2-chloromethyl-4-benzyl amino-quinazolines
R fValue: 0.60 (silica gel, cyclohexane/ethyl acetate=1: 1)
Mass spectrum (ESI +): m/z=284,286[M+H] +
EXAMPLE V
1-brooethyl-4-cyano group-isoquinoline 99.9
By under 80 ℃, in the presence of Diisopropyl azodicarboxylate, in tetracol phenixin, 1-methyl-4-cyano group-isoquinoline 99.9 bromination is prepared with N-bromine succinimide.
R fValue: 0.51 (silica gel, methylene dichloride)
Mass spectrum (ESI +): m/z=246,248[M+H] +
The acquisition and the EXAMPLE V of following compounds are similar:
(1) 2-brooethyl-4-cyano group-quinoline
Mass spectrum (ESI +): m/z=247,249[M+H] +
(2) 3-brooethyl-1-cyano group-isoquinoline 99.9
Mass spectrum (ESI +): m/z=247,249[M+H] +
(3) 1-brooethyl-4-(pyridine-2-yl)-isoquinoline 99.9
R fValue: 0.47 (silica gel, methylene chloride=9: 1)
(4) 2-brooethyl-4-methoxy yl-quinoline
Mass spectrum (ESI +): m/z=252,254[M+H] +
(5) 3-brooethyl-[1,5] naphthyridine
Mass spectrum (ESI +): m/z=223,225[M+H] +
(6) 2-brooethyl-5-cyano group-quinoline
R fValue: 0.28 (silica gel, petrol ether/ethyl acetate=5: 1)
Mass spectrum (ESI +): m/z=247,249[M+H] +
(7) 2-brooethyl-3-cyano group-quinoline
R fValue: 0.65 (silica gel, cyclohexane/ethyl acetate=3: 1)
(8) 2-brooethyl-4-phenyl-pyrimidine
R fValue: 0.88 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=249,251[M+H] +
(9) 2-brooethyl-1,4-dicyano-naphthalene
R fValue: 0.48 (silica gel, petrol ether/ethyl acetate=9: 1)
Mass spectrum (ESI +): m/z=270,272[M+H] +
(10) 2-brooethyl-6,7-dimethoxy yl-quinoline
R fValue: 0.70 (silica gel, methylene chloride=95: 5)
Mass spectrum (ESI +): m/z=282,284[M+H] +
(11) 2-brooethyl-4-cyano group-quinazoline
R fValue: 0.88 (silica gel, methylene chloride=99: 1)
Mass spectrum (ESI +): m/z=247,249[M] +
(12) 7-brooethyl-quinazoline
R fValue: 0.15 (silica gel, methylene chloride=99: 1)
Mass spectrum (ESI +): m/z=223,225[M+H] +
(13) 2-trifluoromethyl-4-cyano group-benzyl bromide
(14) 2-brooethyl-5-cyano group-6-methoxyl group-pyridine
Mass spectrum (ESI +): m/z=227,229[M+H] +
(15) 3-brooethyl-4-cyano group-isoquinoline 99.9
R fValue: 0.43 (silica gel, petrol ether/ethyl acetate=7: 3)
(16) 7-brooethyl-8-cyano group-quinoline
R fValue: 0.25 (silica gel, petrol ether/ethyl acetate=7: 3)
Mass spectrum (ESI +): m/z=247,249[M+H] +
(17) 2-brooethyl-8-cyano group-quinoline
R fValue: 0.75 (silica gel, methylene chloride=99: 1)
Mass spectrum (ESI +): m/z=247,249[M+H] +
Example VI
2-bromo-1-(3-encircles propoxy--phenyl)-ethyl ketone
Be prepared by dichloromethane solution bromination 1-(3-encircles propoxy--phenyl)-ethyl ketone under reflux temperature with phenyl trimethylammonium tribromide ammonium.
R fValue: 0.75 (silica gel, cyclohexane/ethyl acetate=3: 1)
Mass spectrum (ESI +): m/z=255,257[M+H] +
The acquisition and the example VI of following compounds are similar:
(1) 2-bromo-1-(3-cyclo propyl methoxy-phenyl)-ethyl ketone
R fValue: 0.70 (silica gel, cyclohexane/ethyl acetate=3: 1)
(2) 2-bromo-1-(3-cyclobutoxy group-phenyl)-ethyl ketone
R fValue: 0.70 (silica gel, cyclohexane/ethyl acetate=3: 1)
Example VII A
1-(3-encircles propoxy--phenyl)-ethyl ketone
At the N of potassiumiodide and potassium tert.-butoxide, under the existence of dinethylformamide,, 3-hydroxy acetophenone (3-hydroxyacetophenone) and brominated propane prepared by being reacted under 220 ℃ in microwave.
R fValue: 0.65 (silica gel, cyclohexane/ethyl acetate=3: 1)
Mass spectrum (ESI +): m/z=177[M+H] +
The acquisition and the example VII A of following compounds are similar:
(1) 1-(3-cyclo propyl methoxy-phenyl)-ethyl ketone
R fValue: 0.70 (silica gel, cyclohexane/ethyl acetate=3: 1)
Mass spectrum (ESI +): m/z=191[M+H] +
(2) 1-(3-cyclobutoxy group-phenyl)-ethyl ketone
R fValue: 0.65 (silica gel, cyclohexane/ethyl acetate=3: 1)
Mass spectrum (ESI +): m/z=191[M+H] +
Example VII A I
1-chloromethyl-2,4-dimethoxy-naphthalene
By under envrionment temperature, the dichloromethane solution of using thionyl chloride is with 1-methylol-2, and 4-dimethoxy-naphthalene chlorination is prepared.
R fValue: 0.78 (silica gel, cyclohexane/ethyl acetate=1: 1)
Mass spectrum (EI): m/z=236,238[M+H] +
Example I X
1-methylol-2,4-dimethoxy-naphthalene
By under envrionment temperature, with 2,4-dimethoxy-naphthalene-1-formaldehyde (carboxaldehyde) also was prepared originally with the mixture of diox sodium borohydride in diox and water (3: 1).
R fValue: 0.48 (silica gel, cyclohexane/ethyl acetate=1: 1)
Embodiment X
1-[(6-amino-quinoline-2-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
By under 55-60 ℃, with the mixture process 1-[(6-nitro-quinoline-2-yl of V-Brite B in ethanol/water (5: 2)) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine is prepared.
R fValue: 0.40 (silica gel, methylene chloride=95: 5)
Mass spectrum (ESI +): m/z=573[M+H] +
Embodiment XI
1-methyl-4-(pyridine-2-yl)-isoquinoline 99.9
1 of Zai diox tetrakis triphenylphosphine palladium, triphenylphosphine, yellow soda ash and cuprous iodide (I), under the existence of 4-dioxane solution, be prepared by 4-bromo-1-methyl-isoquinoline 99.9 and different third oxygen of lithium-three-2-pyridyl-borate (boronate) down in reflux temperature.
R fValue: 0.22 (silica gel, methylene chloride=95: 5)
Mass spectrum (ESI +): m/z=22 1[M+H] +
Embodiment XII
1-[(8-amino-quinoline-2-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Iron powder in the mixture by being used in Glacial acetic acid, second alcohol and water (2: 20: 5) is handled 1-[(8-nitro-quinoline-2-yl down in reflux temperature) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine is prepared.
R fValue: 0.50 (silica gel, methylene chloride=95: 5)
Mass spectrum (ESI +): m/z=573[M+H] +
Embodiment XIII
1-{2-oxo-2-[2-(pyridin-3-yl)-phenyl]-ethyl }-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Under four (trimethyl-phosphine) palladium in the mixture of toluene/ethanol (1: 1), four-normal-butyl bromination ammonium and yellow soda ash exist, in 105 ℃ down by with 1-[2-oxo-2-(2-bromo-phenyl)-ethyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine and pyridine-3-acid reaction be prepared.
R fValue: 0.55 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=612[M+H] +
The acquisition of following compounds and embodiment XII are similar:
(1) 1-{2-oxo-2-[2-(pyridin-4-yl)-phenyl]-ethyl }-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
(reaction is to carry out with 4-(4,4,5, the 5-tetramethyl--luxuriant alkane of [1,3,2] dioxo bora (dioxaborolan)-2-yl)-pyridine)
R fValue: 0.40 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=612[M+H] +
Embodiment XIV
1-[(4-ethyl-quinazoline-2-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
By handling 1-cyano methyl-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl with the methanol solution of potassium tert.-butoxide]-xanthine and exist down the imines ester of gained and 2-amino-Propiophenone reacted in acetic acid subsequently and be prepared.
R fValue: 0.60 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=587[M+H] +
The acquisition of following compounds and embodiment XIV are similar:
(1) methyl 1-[(4-cyclopropyl-quinazoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
R fValue: 0.70 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=599[M+H] +
Embodiment XV
2-chloromethyl-3-cyano group-4-methyl-quinoline
By under 80 ℃, make 3-cyano group-2, the toluene solution of 4-dimethyl-1-oxy-quinoline and benzene sulfinyl chlorine (benzosulphonic acid chloride) reacts and is prepared.
R fValue: 0.55 (silica gel, cyclohexane/ethyl acetate=2: 1)
Mass spectrum (ESI +): m/z=217,219[M+H] +
Embodiment XVI
3-cyano group-2,4-dimethyl-1-oxy-quinoline
By under 60 ℃, the aqueous hydrogen peroxide solution (35%) that is used in the Glacial acetic acid is handled 3-cyano group-2, and 4-diformazan yl-quinoline is prepared.
R fValue: 0.35 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=199[M+H] +
Embodiment XVII
2-chloromethyl-4,5-dimethyl-quinazoline
By under 30-38 ℃, 1-(2-amino-6-methyl-phenyl)-ethyl ketone and chloromethyl cyanide are reacted in diox be prepared.
Mass spectrum (ESI +): m/z=207,209[M+H] +
Embodiment XVIII
1-[(2-methyl-quinazoline-4-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
By making 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine and ethanol ammonia (ehtanolicammonia) (6M) and ammonium chloride be prepared at 150 ℃ pressure cooker internal reaction.
R fValue: 0.35 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=573[M+H] +
Embodiment XIX
1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
By under envrionment temperature, when pyridine exists, make 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine and Acetyl Chloride 98Min. react in methylene dichloride and be prepared.
R fValue: 0.79 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=592[M+H] +
Embodiment XX
1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyne-1-yl)-8-I (R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
By under envrionment temperature, in tetrahydrofuran (THF) with tin chloride (II) dihydrate with 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine also was prepared originally.
R fValue: 0.85 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=550[M+H] +
Embodiment XXI
1-[(furans-3-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl with 300mg]-xanthine, 95 μ l furans-3-base-methyl alcohol, 302mg triphenylphosphine and the mixture of 226 μ l diisopropyl azo-2-carboxylic acids in the 4ml tetrahydrofuran (THF) stir under envrionment temperature and spend the night.Then this reaction mixture and unsaturated carbonate potassium solution are merged and extracted with ethyl acetate.The organic phase that merges is also evaporated through dried over mgso.Residue in the reaction flask is carried out chromatography through silicagel column with cyclohexane/ethyl acetate (1: 1 to 3: 7).
Output: 330mg (theoretical 92%)
Mass spectrum (ESI +): m/z=497[M+H] +
The acquisition of following compounds and embodiment XXI are similar:
(1) methyl 1-[(5-methyl-furans-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-bromo-xanthine
Mass spectrum (ESI +): m/z=391,393[M+H] +
(2) methyl 1-[(5-bromo-furans-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
Mass spectrum (ESI +): m/z=575,577[M+H] +
Embodiment XXII
1-[(5-cyano group-furans-2-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine
By under reflux temperature, make 1-[(5-formyl radical-furans-2-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(t-butoxycarbonyl amino)-piperidines-1-yl]-xanthine and hydroxylamine-o-sulfonic acid and pyridine react in toluene and be prepared.
Embodiment XXIII
5-(mesyloxy methyl)-2-furans-formaldehyde
By at ambient temperature, under triethylamine exists, make 5-(methylol)-2-furans-formaldehyde and methylsulfonyl chloride under the triethylamine existence, in methylene dichloride, react and be prepared.Crude product can further react without any being further purified.
Embodiment XXIV
2-chloromethyl-2-cyano group-pyridine
By make 2-(methylol)-niacinamide in acetonitrile with thionyl chloride reaction, and subsequently under triethylamine exists, in methylene dichloride with trifluoro-acetic anhydride with 2-(chloromethyl)-niacinamide dehydration of gained and make.
Perhaps, this compound also can be by 2-(methylol)-niacinamide is refluxed with Phosphorus Oxychloride a step make.
R fValue: 0.85 (silica gel, methylene chloride=9: 1)
Mass spectrum (ESI +): m/z=153,155[M+H] +
Embodiment XXV
8-cyano group-7-methyl-quinoline
By under 100-105 ℃, make 8-bromo-7-methyl-quinoline in the presence of the N-Methyl pyrrolidone solution of four (trimethyl-phosphine) palladium, in protective gas, react and be prepared with cyano group zinc.
R fValue: 0.35 (silica gel, petrol ether/ethyl acetate=7: 3)
Mass spectrum (ESI +): m/z=169[M+H] +
Embodiment XXVI
2-methyl-8-cyano group-quinoline
By under 180 ℃, in protective gas, the N-Methyl pyrrolidone solution reaction of 2-methyl-8-bromo-quinoline and cyano groupization cuprous (I) is prepared.
R fValue: 0.40 (silica gel, petrol ether/ethyl acetate=7: 3)
Mass spectrum (ESI +): m/z=169[M+H] +
The preparation of final compound
Embodiment 1
1-[(4-phenyl amino-quinazoline-2-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-amino-piperadine-1-yl)-xanthine
1-[(4-phenyl amino-quinazoline-2-yl with 400mg) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[3-(t-butoxycarbonyl amino)-piperidines-1-yl]-mixture and the 2ml Virahol hydrochloric acid (isopropanolic hydrochloric acid) of xanthine in the 10ml methylene dichloride (5-6M) merges and stirred under envrionment temperature 3 hours.Dilute this reaction mixture with methylene dichloride again, it and frozen water are merged and make alkalize with the 3M wet chemical.With water with dichloromethane extraction.Extract so that water washing merges also evaporates through dried over mgso.Residue in the bottle is stirred with ether, and suction filtration is with ether washing and dry in vacuum.
Output: 274mg (theoretical 81%)
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=550[M+H] +
The acquisition of following compounds is similar to Example 1:
(1) methyl 1-[(4-benzyl amino-quinazolines-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-(3-amino-piperadine-1-yl)-xanthine
R fValue: 0.43 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=564[M+H] +
(2) methyl 1-[(2-methyl-quinolyl-4)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
Mass spectrum (ESI +): m/z=472[M+H] +
(3) methyl 1-[(3-cyano group-naphthalene-1-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.55 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=482[M+H] +
(4) methyl 1-[(2-phenyl-quinazoline-4-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.45 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=535[M+H] +
(5) methyl 1-[(4-cyano group-isoquinolyl-1)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.15 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=483[M+H] +
(6) methyl 1-[(4-cyano group-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
Mass spectrum (ESI +): m/z=483[M+H] +
(7) 1-[2-(3-encircles propoxy--phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.45 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=491[M+H] +
(8) 1-[2-(3-cyclo propyl methoxy-phenyl)-2-oxygen base-ethyl]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.35 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=505[M+H] +
(9) 1-[2-(3-cyclobutoxy group-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.40 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=5 05[M+H] +
(10) methyl 1-[(1-cyano group-isoquinoline 99.9-3-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
Mass spectrum (ESI +): m/z=483[M+H] +
(11) 1-[(2,4-methoxyl group-naphthalene-1-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.55 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=517[M+H] +
(12) 1-[(2,3-dimethyl-quinoxalin-6-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.48 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=487[M+H] +
(13) methyl 1-[(6-amino-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.40 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=473[M+H] +
(14) methyl 1-[(quinoxaline-5-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine-hydrochloride
Mass spectrum (ESI +): m/z=459[M+H] +
(15) methyl 1-[(6-methoxy yl-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=488[M+H] +
(16) methyl 1-[(6-phenyl-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.37 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=484[M+H] +
(17) 1-{[(4-(pyridine-2-yl)-isoquinolyl-1] methyl }-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.37 (silica gel, methylene chloride/concentrated ammonia solution=80: 20: 1)
Mass spectrum (ESI +): m/z=535[M+H] +
(18) methyl 1-[(7-fluoro-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.58 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=476[M+H] +
(19) methyl 1-[(8-amino-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=473[M+H] +
(20) methyl 1-[(6-fluoro-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=476[M+H] +
(21) 1-{2-oxygen base-2-[2-(pyridin-3-yl)-phenyl]-ethyl }-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.55 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=512[M+H] +
(22) methyl 1-[(4-ethyl-quinazoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.45 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=487[M+H] +
(23) methyl 1-[(4-cyclopropyl-quinazoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.45 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=499[M+H] +
(24) methyl 1-[(4-methoxy yl-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
Mass spectrum (ESI +): m/z=488[M+H] +
(25) methyl 1-[(2-phenyl-pyrimidine-4-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=485[M+H] +
(26) 1-[([1,5] naphthyridine-3-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.52 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=459[M+H] +
(27) methyl 1-[(3-cyano group-4-methyl-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.50 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=497[M+H] +
(28) 1-[(4,5-dimethyl-quinazoline-2-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=487[M+H] +
(29) methyl 1-[(5-cyano group-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=483[M+H] +
(30) methyl 1-[(3-cyano group-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.50 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=483[M+H] +
(31) methyl 1-[(4-phenyl-pyrimidine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=485[M+H] +
(32) methyl 1-[(2-methyl-quinazoline-4-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.38 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=473[M+H] +
(33) 1-[(1,4-dicyano-naphthalene-2-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine-hydrochloride
R fValue: 0.86 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=507[M+H] +
(34) 1-{2-oxo-2-[2-(pyridin-4-yl)-phenyl]-ethyl }-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.55 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=512[M+H] +
(35) 1-[(6,7-dimethoxy yl-quinoline-2-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.45 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=518[M+H] +
(36) methyl 1-[(quinazoline-6-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine-hydrochloride
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=459[M+H] +
(37) methyl 1-[(4-cyano group-quinazoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=484[M+H] +
(38) methyl 1-[(quinazoline-7-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.43 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=459[M+H] +
(39) 1-(2-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.35 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=432[M+H] +
(40) 1-(3-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.40 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=432[M+H] +
(41) 1-(4-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.31 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=432[M+H] +
(42) methyl 1-[(pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.52 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=408[M+H] +
(43) 1-benzyl-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Fusing point: 207-209 ℃
Mass spectrum (ESI +): m/z=407[M+H] +
(44) 1-(4-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine-hydrochloride
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=43 7[M+H] +
(45) 1-(2-chloro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=441,443[M+H] +
(46) 1-(2,6-dicyano-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine * trifluoracetic acid
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=457[M+H] +
(47) 1-(2-cyano group-4-bromo-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine * trifluoracetic acid
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=510,512[M+H] +
(48) 1-(3-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.45 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=425[M+H] +
(49) 1-(3,5-dimethoxy-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.45 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=467[M+H] +
(50) 1-(2-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.45 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=425[M+H] +
(51) methyl 1-[(6-cyano group-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=43 3[M+H] +
(52) methyl 1-[(3-cyano group-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=433[M+H] +
(53) 1-(2-cyano group-3-chloro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine * trifluoracetic acid
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=466,468[M+H] +
(54) 1-(4-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=425[M+H] +
(55) 1-(4-chloro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=441,443[M+H] +
(56) 1-(2-cyano group-4-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine * trifluoracetic acid
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=450[M+H] +
(57) 1-(3-cyano group-4-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine * trifluoracetic acid
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=450[M+H] +
(58) 1-(2-chloro-4-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine * trifluoracetic acid
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=466,468[M+H] +
(59) methyl 1-[(5-methoxycarbonyl-furans-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine * trifluoracetic acid
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=455[M+H] +
(60) 1-(2-trifluoromethyl-4-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine * trifluoracetic acid
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=500[M+H] +
(61) 1-(3,5-dicyano-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=457[M+H] +
(62) 1-(3-nitro-4-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine * trifluoracetic acid
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=477[M+H] +
(63) methyl 1-[(2-cyano group-pyridin-3-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.50 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=433[M+H] +
(64) 1-(2-cyano group-4-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.50 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=462[M+H] +
(65) 1-(2-cyano group-5-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.45 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=462[M+H] +
(66) 1-(3-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.45 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=437[M+H] +
(67) 1-(3-trifluoromethyl-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.60 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=475[M+H] +
(68) 1-(3,4-dimethoxy-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=467[M+H] +
(69) 1-(3-chloro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.45 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=441,443[M+H] +
(70) 1-(4-trifluoromethyl-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.45 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=475[M+H] +
(71) 1-[([2,2 '] bipyridyl-6-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=485[M+H] +
(72) 1-(3,4-dimethoxy-6-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=485[M+H] +
(73) methyl 1-[(6-fluoro-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.41 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=426[M+H] +
(74) methyl 1-[(5-cyano group-6-methoxyl group-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.40 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=463[M+H] +
(75) 1-(2,6-two fluoro-benzyls)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.41 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=443[M+H] +
(76) 1-(3-trifluoromethoxy-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.36 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=491[M+H] +
(77) 1-(4-trifluoromethoxy-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.38 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=491[M+H] +
(78) methyl 1-[(2-cyano group-pyridin-4-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.60 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=433[M+H] +
(79) methyl 1-[(5-cyano group-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.60 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=433[M+H] +
(80) methyl 1-[(pyrimidine-2-base)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.60 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=409[M+H] +
(81) methyl 1-[(4-methyl-pyrimidine-2-base)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.65 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=423[M+H] +
(82) 1-[(4,6-dimethyl-pyrimidine-2-base) methyl]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Fusing point: 202-204 ℃
Mass spectrum (ESI +): m/z=437[M+H] +
(83) methyl 1-[(quinoxalin-6-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=459[M+H] +
(84) 1-(3-fluoro-4-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.45 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=455[M+H] +
(85) 1-(3,4-two fluoro-benzyls)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.45 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=443[M+H] +
(86) 1-(2-fluoro-5-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.39 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=455[M+H] +
(87) 1-(2-fluoro-3-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.41 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=455[M+H] +
(88) methyl 1-[(4-cyano group-isoquinoline 99.9-3-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.40 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=483[M+H] +
(89) 1-(2-fluoro-4-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.45 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 1)
Mass spectrum (ESI +): m/z=455[M+H] +
(90) methyl 1-[(furans-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-(R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=397[M+H] +
(91) 1-(3,4-dicyano-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine * trifluoracetic acid
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=457[M+H] +
(92) methyl 1-[(furans-3-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=397[M+H] +
(93) methyl 1-[(5-methyl-furans-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=411[M+H] +
(94) methyl 1-[(5-bromo-furans-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine * trifluoracetic acid
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=475,477[M+H] +
(95) 1-(4-cyano group-2-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=450[M+H] +
(96) 1-(2-cyano group-5-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=450[M+H] +
(97) methyl 1-[(5-cyano group-furans-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine * trifluoracetic acid
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=422[M+H] +
(98) 1-(2-cyano group-6-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=450[M+H] +
(99) 1-(4-cyano group-3-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=450[M+H] +
(100) 1-(2-cyano group-3-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=462[M+H] +
(101) methyl 1-[(8-cyano group-quinoline-7-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Mass spectrum (ESI +): m/z=483[M+H] +
(102) methyl 1-[(4-cyano group-pyridin-3-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
Fusing point: 166 ℃
Mass spectrum (ESI +): m/z=43 3[M+H] +
(103) methyl 1-[(8-cyano group-quinoline-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.50 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=483[M+H] +
(104) methyl 1-[(1-methyl isophthalic acid H-benzotriazole-5-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.60 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=462[M+H] +
(105) methyl 1-[(3-cyano group-pyridin-4-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine * trifluoracetic acid
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.65 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=433[M+H] +
(106) methyl 1-[(3-cyano group-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((S)-3-amino-piperadine-1-yl)-xanthine
(carrying out BOC with trifluoracetic acid removes)
R fValue: 0.60 (ready-made anti-phase TLC plate (E.Merck), acetonitrile/water/trifluoracetic acid=50: 50: 1)
Mass spectrum (ESI +): m/z=433[M+H] +
(107) methyl 1-[(4-cyano group-benzo [1,3] dioxole-5-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
R fValue: 0.45 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1)
Mass spectrum (ESI +): m/z=476[M+H] +
Following compounds also can similar previous embodiment and the additive method learnt from document obtain:
(1) 1-(2-cyano group-4-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(2) 1-(2-cyano group-5-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(3) 1-(2-cyano group-6-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(4) 1-(3-cyano group-4-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(5) 1-(3,5-dicyano-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(6) 1-(3,4-dicyano-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(7) 1-(3-nitro-4-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(8) 1-(2-chloro-4-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(9) 1-(2-fluoro-4-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(10) 1-(2-trifluoromethyl-4-cyano group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(11) methyl 1-[(5-cyano group-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(12) methyl 1-[(4-cyano group-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(13) methyl 1-[(4-cyano group-pyridin-3-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(14) methyl 1-[(3-cyano group-pyridin-4-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(15) methyl 1-[(2-cyano group-pyridin-3-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(16) methyl 1-[(2-cyano group-pyridin-4-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(17) methyl 1-[(5-cyano group-pyridin-3-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(18) methyl 1-[(6-cyano group-pyridin-3-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(19) 1-(2-cyano group-4-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(20) 1-(2-cyano group-5-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(21) 1-[([2,2 '] bipyridyl-6-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(22) methyl 1-[(5-methoxyl group-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(23) methyl 1-[(6-fluoro-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(24) methyl 1-[(5-cyano group-6-methoxyl group-pyridine-2-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(25) 1-(2-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(26) 1-(3-methoxyl group-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(27) 1-(3-chloro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(28) 1-(4-trifluoromethyl-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(29) 1-(3-trifluoromethyl-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(30) 1-(2-trifluoromethyl-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(31) 1-(3,4-dimethoxy-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(32) 1-(3,4-dimethoxy-6-fluoro-benzyl)-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
(33) methyl 1-[(benzo [1,3] dioxole-5-yl)]-3-methyl-7-(2-butyne-1-yl)-8-((R)-3-amino-piperadine-1-yl)-xanthine
Embodiment 2
The coating tablet that contains the 75mg active substance
1 label comprises:
Active substance 75.0mg
Calcium phosphate 93.0mg
W-Gum 35.5mg
Polyvidone 10.0mg
Vltra tears 15.0mg
Magnesium Stearate 1.5mg
230.0mg
Preparation:
Half Magnesium Stearate of active substance and calcium phosphate, W-Gum, polyvidone, Vltra tears and specified quantitative is mixed.In pelleter, it is made the empty ingot that diameter is about 13mm and re-use suitable machine, be the screen cloth of 1.5mm with its friction by mesh size and mix with remaining Magnesium Stearate.In pelleter, this particle is pressed into the tablet of desired shape.
Core is heavy: 230mg
Mould circle (die): 9mm, convex surface
The label that makes is thus carried out dressing with the film of being made up of Vltra tears basically.Tablet through the film dressing polishes with beeswax again.
Coating tablet is heavy: 245mg
Embodiment 3
The tablet that contains the 100mg active substance
Composition:
1 tablet comprises:
Active substance 100.0mg
Lactose 80.0mg
W-Gum 34.0mg
Polyvidone 4.0mg
Magnesium Stearate 2.0mg
220.0mg
The preparation method:
Active substance, lactose and starch mixed and evenly wetting in addition with the aqueous solution of polyvidone.The composition that should wet sieve (2.0mm mesh size) and in rack type drying machine with 50 ℃ in addition after the drying, sieve once more (1.5mm mesh size) and add lubricant.The mixture compacting of gained is in blocks.
Tablet weight: 220mg
Diameter: 10mm, two-sided, carve on the two sides and single face cuts a notch.
Embodiment 4
The tablet that contains the 150mg active substance
Composition:
1 tablet comprises:
Active substance 150.0mg
Powdered lactose 89.0mg
W-Gum 40.0mg
Silica colloidal 10.0mg
Polyvidone 10.0mg
Magnesium Stearate 1.0mg
300.0mg
Preparation:
Will with lactose, W-Gum and silicon-dioxide blended active substance with 20% polyvidone aqueous solution in addition wetting and sieve through the screen cloth of 1.5mm mesh size.Make to rescreen through same screen cloth and with the Magnesium Stearate of specified quantitative and mix through 45 ℃ of following dry granules.With this mixture compacting in flakes.
Tablet weight: 300mg
Mould circle: 10mm, plain film
Embodiment 5
The hard gelatin capsule that contains the 150mg active substance
1 capsule comprises:
Active substance 150.0mg
The about 180.0mg of W-Gum (drying)
The about 87.0mg of lactose (through efflorescence)
Magnesium Stearate 3.0mg
About 420.0mg
Preparation:
With active substance and mixed with excipients, sieve is through the screen cloth of 0.75mg mesh size and use suitable equipment with it uniform mixing.The gained mixture is packed in No. 1 hard gelatin capsule.
Capsule is filled: about 320mg
Capsule shell: No. 1 hard gelatin capsule
Embodiment 6
The suppository that contains the 150mg active substance
1 suppository comprises:
Active substance 150.0mg
Polyethylene glycol 1500 550.0mg
Polyethylene glycol 6000 460.0mg
Polyoxyethylene 20 sorbitan monostearate 840.0mg
2,000.00mg
Preparation:
After the thawing of suppository raw material, make active substance be uniformly distributed in wherein and should melt thing and pour in the chill mould.
Embodiment 7
The suspension that contains the 50mg active substance
The suspension of 100ml contains:
Active substance 1.00g
Carboxymethyl cellulose-Na-salt 0.10g
Methyl p-hydroxybenzoate 0.05g
Propylparaben 0.01g
Glucose 10.00g
Glycerine 5.00g
70% Sorbitol Solution USP 20.00g
Correctives 0.30g
Distilled water adds to 100ml
Preparation:
Distilled water is heated to 70 ℃.With methyl p-hydroxybenzoate and propyl ester therein with the sodium salt stirring and dissolving of glycerine and carboxymethyl cellulose.This solution is cooled to envrionment temperature and adds active substance and stir and make its homodisperse therein.Add after the sugar, add Sorbitol Solution USP and correctives and dissolving again, the stirred suspension exhaust is to eliminate air.
The suspension of 5ml contains the 50mg active substance.
Embodiment 8
The ampoule that contains the 10mg active substance
Composition:
Active substance 10.0mg
0.01N hydrochloric acid is an amount of
Bi-distilled water is to 2.0ml
Preparation:
Active substance is dissolved among the 0.01N HCl of aequum, transfers to etc. with salt and open, filtration sterilization also is transferred in the 2ml ampoule.
Embodiment 9
The ampoule that contains the 50mg active substance
Composition:
Active substance 50.0mg
0.01N hydrochloric acid is an amount of
Bi-distilled water adds to 10.0ml
Preparation:
Active substance is dissolved among the 0.01N HCl of aequum, transfers to etc. with salt and open, filtration sterilization also is transferred in the 10ml ampoule.

Claims (8)

1. the compound of following general formula, its tautomer, enantiomer, diastereomer, mixture and salt,
Figure A2005800054230002C1
Wherein
R represents benzyl, 2-luorobenzyl, 3-luorobenzyl, 4-luorobenzyl, 2,6-two fluoro-benzyls, 3, and 4-two fluoro-benzyls, 2-benzyl chloride base, 3-benzyl chloride base or 4-benzyl chloride base group,
2-trifluoromethyl-benzyl, 3-trifluoromethyl-benzyl or 4-trifluoromethyl-benzyl group,
3-trifluoromethoxy-benzyl or 4-trifluoromethoxy-benzyl group,
2-cyano group benzyl, 3-cyano group benzyl or 4-cyano group benzyl group,
2,6-dicyano benzyl, 3,4-dicyano benzyl, 3,5-dicyano benzyl, 2-trifluoromethyl-4-cyano group-benzyl, 3-nitro-4-cyano group-benzyl, 2-cyano group-3-methoxyl group-benzyl, 2-cyano group-4-methoxyl group-benzyl, 2-cyano group-5-methoxyl group-benzyl, 2-cyano group-4-fluoro-benzyl, 2-cyano group-5-fluoro-benzyl, 2-cyano group-6-fluoro-benzyl, 3-cyano group-4-fluoro-benzyl, 4-cyano group-3-fluoro-benzyl, 2-fluoro-4-cyano group-benzyl, 2-cyano group-3-benzyl chloride base, 2-chloro-4-cyano group-benzyl or 2-cyano group-4-bromobenzyl group
2-methoxyl group-benzyl, 3-methoxyl group-benzyl, 4-methoxyl group-benzyl, 2-fluoro-3-methoxyl group-benzyl, 2-fluoro-4-methoxyl group-benzyl, 2-fluoro-5-methoxyl group-benzyl, 3-fluoro-4-methoxyl group-benzyl, 3,4-dimethoxy-benzyl, 3,5-veratryl or 3,4-dimethoxy-6-fluoro-benzyl group
(benzo [1,3] dioxole-5-yl) methyl group,
[(4-cyano group-benzo [1,3] dioxole-5-yl) methyl group,
2-(3-encircles propoxy--phenyl)-2-oxo-ethyl, 2-(3-cyclo propyl methoxy-phenyl)-2-oxo-ethyl or 2-(3-cyclobutoxy group-phenyl)-2-oxo-ethyl group,
2-oxo-2-[2-(pyridin-3-yl)-phenyl]-ethyl or 2-oxo-2-[2-(pyridin-4-yl)-phenyl]-ethyl group,
(3-cyano group-naphthalene-1-yl) methyl, (1,4-dicyano-naphthalene-2-yl) methyl or (2,4-dimethoxy-naphthalene-1-yl) methyl group,
(furans-2-yl) methyl, (furans-3-yl) methyl, (5-bromo-furans-2-yl) methyl, (5-methyl-furans-2-yl) methyl, (5-cyano group-furans-2-yl) methyl or (5-methoxycarbonyl-furans-2-yl) methyl group,
(pyridine-2-yl) methyl, (6-fluoro-pyridine-2-yl) methyl or (5-methoxyl group-pyridine-2-yl) methyl group,
(3-cyanopyridine-2-yl) methyl, (6-cyanopyridine-2-yl) methyl, (5-cyano group-pyridine-2-yl) methyl, (4-cyano group-pyridine-2-yl) methyl, (4-cyano group-pyridin-3-yl) methyl, (3-cyano group-pyridin-4-yl) methyl, (2-cyano group-pyridin-3-yl) methyl, (2-cyano group-pyridin-4-yl) methyl, (5-cyano group-pyridin-3-yl) methyl, (6-cyano group-pyridin-3-yl) methyl or (5-cyano group-6-methoxyl group-pyridine-2-yl) methyl group
(6-phenyl-pyridine-2-yl) methyl or ([2,2 '] dipyridyl-6-yl) methyl group,
(pyrimidine-2-base) methyl, (4-methyl-pyrimidine-2-base) methyl or (4,6-dimethyl-pyrimidine-2-base) methyl group,
(2-phenyl-pyrimidine-4-yl) methyl or (4-phenyl-pyrimidine-2-yl) methyl group,
[(1-methyl isophthalic acid H-benzotriazole-5-yl) methyl] group,
(6-fluoro-quinoline-2-yl) methyl, (7-fluoro-quinoline-2-yl) methyl, (2-methyl-quinolyl-4) methyl, (3-cyano group-quinoline-2-yl) methyl, (3-cyano group-4-methyl-quinoline-2-yl) methyl, (4-cyano group-quinoline-2-yl) methyl, (5-cyano group-quinoline-2-yl) methyl, (8-cyano group-quinoline-2-yl) methyl, (6-amino-quinoline-2-yl) methyl, (8-amino-quinoline-2-yl) methyl, (4-methoxy yl-quinoline-2-yl) methyl, (6-methoxy yl-quinoline-2-yl) methyl, (6,7-dimethoxy yl-quinoline-2-yl) methyl or (8-cyano group-quinoline-7-yl) methyl group
(1-cyano group-isoquinoline 99.9-3-yl) methyl, (4-cyano group-isoquinolyl-1) methyl-(4-cyano group-isoquinoline 99.9-3-yl) methyl or [(4-(pyridine-2-yl)-isoquinolyl-1] methyl group,
(quinazoline-6-yl) methyl, (quinazoline-7-yl) methyl, (2-methyl-quinazoline-4-yl) methyl, (4,5-dimethyl-quinazoline-2-yl) methyl, (4-ethyl-quinazoline-2-yl) methyl, (4-cyclopropyl-quinazoline-2-yl) methyl, (2-phenyl-quinazoline-4-yl) methyl, (4-cyano group-quinazoline-2-yl) methyl, (4-phenyl amino-quinazoline-2-yl) methyl or (4-benzyl amino-quinazolines-2-yl) methyl group
(quinoxaline-5-yl) methyl-(quinoxalin-6-yl) methyl or (2,3-dimethyl-quinoxalin-6-yl) methyl group, or
([1,5] naphthyridine-3-yl) methyl group.
2. compound of following general formula, and tautomer and salt:
The wherein definition in R such as the claim 1.
3. the compound of following general formula, and tautomer and its salt:
Figure A2005800054230004C2
Wherein R definition as claimed in claim 1.
4. as at least one the compound and the physiologically acceptable salt of organic or inorganic acid in the claim 1 to 3.
5. comprise pharmaceutical composition, its optional one or more inert supports and/or thinner of containing as the physiologically acceptable salt of at least one compound in the claim 1 to 3 or claim 4.
6. as at least one the purposes of compound in pharmaceutical compositions in the claim 1 to 4, this pharmaceutical composition is to be fit to treatment I type and type ii diabetes, sacroiliitis, obesity, allotransplantation and thyrocalcitonin inductive osteoporosis.
7. be used to prepare the method for the pharmaceutical composition of claim 5, it is characterized in that by property method non-chemically with at least one compound in the claim 1 to 4 in one or more inert supports and/or thinner.
8. at least one the method for compound of Formula I in the preparation claim 1 to 4 is characterized in that:
A) make as shown in the formula compound and 3-amino piperidine, its enantiomer or reactant salt,
Figure A2005800054230005C1
Wherein
Definition in R such as the claim 1, and
Z 1Represent leavings group, for example: the hydroxyl of halogen atom, replacement, sulfydryl, sulfinyl, alkylsulfonyl or sulfonyloxy group,
Or
B) compound with following general formula goes protecting group
Figure A2005800054230005C2
The wherein definition in R such as the claim 1, and/or
Any blocking group used between the reaction period is removed, and/or
The compound of Formula I that obtains is like this split into its enantiomer and/or diastereomer, and/or
The compound of Formula I that obtains is like this changed into its salt with inorganic or organic acid, particularly be transformed into its physiologically acceptable salt at pharmaceutical use.
CN2005800054231A 2004-02-18 2005-02-12 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and the use in the form of a DPP-IV inhibitor Active CN1980930B (en)

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DE102004012921A DE102004012921A1 (en) 2004-03-17 2004-03-17 New 7-butynyl-8-(3-amino-1-piperidinyl)xanthine derivatives useful as dipeptidyl peptidase IV inhibitors, e.g. for treating diabetes, arthritis, obesity and osteoporosis
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DE102004032263A DE102004032263A1 (en) 2004-07-03 2004-07-03 New 7-butynyl-8-(3-amino-1-piperidinyl)xanthine derivatives useful as dipeptidyl peptidase IV inhibitors, e.g. for treating diabetes, arthritis, obesity and osteoporosis
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