CN1700911A - Combination drug - Google Patents

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CN1700911A
CN1700911A CN 03825394 CN03825394A CN1700911A CN 1700911 A CN1700911 A CN 1700911A CN 03825394 CN03825394 CN 03825394 CN 03825394 A CN03825394 A CN 03825394A CN 1700911 A CN1700911 A CN 1700911A
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methyl
piperazine
chemical compound
group
reaction
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安田信之
山崎一斗
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R&amp D Management Co., Ltd.
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Eisai Co Ltd
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Abstract

The present invention provides pharmaceutical agents comprising a dipeptidyl peptidase IV (DPPIV) inhibitor and a biguanide agent in combination, which enhance the effects of active circulating glucagon-like peptide-1 (GLP-1) and/or active circulating glucagon-like peptide-2 (GLP-2).

Description

And use medicine
Technical field
The present invention relates to comprise the pharmaceutical preparation of DPP IV (DPPIV) inhibitor and biguanide reagent, the effect of active form glucagon-like-peptide-2 (GLP-2) in active form (active circulating) glucagon-like-peptide-1 (GLP-1) and/or the blood in its enhancing blood.
Background technology
Glucagon-like-peptide-1 (GLP-1) is a kind of known hormone that makes the L emiocytosis of small intestinal bottom owing to ingesting.It has improved mode with glucose-dependence by excreting insulin in the pancreatic beta cell.GLP-1 can be decomposed and quick inactivating by DPP IV (DPPIV).Therefore, the DPPIV inhibitor can be used as the medicine that prevents and/or treats with the concentration dependent disease of GLP-1 such as diabetes (particularly type ii diabetes) and obesity.The DPPIV inhibitor has been studied in clinical trial and has been disclosed in patent documentation 1,2 and 3.
Usually metformin, biguanide reagent are with doing diabetes mellitus prevention and/or curative drug.
Recently, successfully reported new discovery: the GLP-1 concentration when giving metformin (non-patent literature 1) among the fat ND increases; And metformin and GLP-1 and with treating type ii diabetes (non-patent literature 2) effectively.Yet,, by DPPIV GLP-1 is decomposed and inactivation fast as mentioned above even the concentration of GLP-1 only increases momently by metformin.Therefore the raising of GLP-1 concentration does not have long persistency, and thereby has extremely reduced the effect of GLP-1.This point is the problem that will solve.
Non-patent literature 3 and 4 has proposed the scope of application of DPPIV inhibitor and metformin and usefulness.Patent documentation 4-8 has described also using of DPPIV inhibitor and biguanide reagent.Yet these documents are open and with the concrete result of the test of these medicines.In other words, the also usefulness medicine (combination drug) that contains DPPIV inhibitor and metformin that does not have the known GLP-1 of enhancing effect.
Also reported identical with GLP-1, glucagon-like-peptide-2 (GLP-2) is a kind of hormone that makes the L emiocytosis of small intestinal bottom owing to ingesting, and it can be used for preventing and/or treating gastrointestinal disease (patent documentation 5-9).Yet,, GLP-2 is decomposed and inactivation fast by DPPIV as GLP-1.As a result, need exploitation can suppress GLP-2 and decompose, also therefore improve the medicine of GLP-2 effect.Yet report has been described the increase of GLP ' 2 concentration when giving metformin or by effect DPPIV inhibitor and metformin and that be used for promoting GLP-2.
[patent documentation 1]
U.S. Patent number 6166063
[patent documentation 2]
U.S. Patent number 6011155
[patent documentation 3]
U.S. Patent number 6548481
[patent documentation 4]
WO01/52825
[patent documentation 5]
WO01/97808
[patent documentation 6]
Application No. 2002/0161001
[patent documentation 7]
Application No. 2002/0198205
[patent documentation 8]
Application No. 2003/0105077
[non-patent literature 1]
Edoardo Mannucci and 8 other authors, " Diabetes Care ", 24 (3): 489-494 (2001) Mar.
[non-patent literature 2]
Mette Zander and 4 other authors, " Diabetes Care ", 24 (4): 720-725 (2001) Apr.
[non-patent literature 3]
Simon A.Hinke and 5 other authors, " Biochemical and Biophysical ResearchCommunications ", 291 (5): 1302-1308 (2002) Mar.
[non-patent literature 4]
Simon A.Hinke and 9 other authors, " Diabetes Care ", 25 (8): 1490-1491 (2002) Aug.
[non-patent literature 5]
Robin P.Boushey and 2 other authors, " American Journal of Physiology ", 277 (8): E937-E947 (1999)
[non-patent literature 6]
D.L.Sigalet，”Current?Opinion?in?Investigational?Drugs”，2(4)：505-509(2001)Apr.
[non-patent literature 7]
Daniel?J.Drucker，“Gut”，50(3)：428-435(2002)
[non-patent literature 8]
DanielJ.Drucker“Gastroenterology”，122(2)：531-544(2002)Feb.
[non-patent literature 9]
Robin P.Boushey and 2 other authors, " Cancer Research ", 61:687-693 (2001) Jan.
Summary of the invention
An object of the present invention is to provide a kind of pharmaceutical preparation, strengthen the pharmacotoxicological effect of active form GLP-2 in active form GLP-1 in the blood and/or the blood when it can be worked as concentration and increases owing to biguanide reagent by the decomposition that suppresses GLP-1 and/or GLP-2.
Consider above-mentioned background, the present inventor has carried out deep research, and has disclosed the pharmacotoxicological effect that being used in combination of DPPIV inhibitor and biguanide reagent can strengthen active form GLP-2 in active form GLP-1 in the blood and/or the blood.It is because the DPPIV inhibitor can suppress the decomposition of active form GLP-2 in active form GLP-1 in the blood when concentration increases owing to biguanide reagent and/or the blood.Therefore, the present inventor has finished the present invention.
Particularly, the invention provides:
＜1〉comprises the pharmaceutical preparation of inhibitors of dipeptidyl IV and biguanide reagent and usefulness;
＜2〉according to＜1〉pharmaceutical preparation, it can strengthen the effect of active form glucagon-like-peptide-2 (GLP-2) in active form glucagon-like-peptide-1 (GLP-1) in the blood and/or the blood;
＜3〉can strengthen the pharmaceutical preparation of active form GLP-2 effect in the blood;
＜4〉comprise inhibitors of dipeptidyl IV and according to＜3 pharmaceutical preparation and the pharmaceutical preparation of usefulness;
＜5〉according to＜1〉or＜4 pharmaceutical preparation, wherein this inhibitors of dipeptidyl IV is to be selected from any one following chemical compound:
(S)-1-((3-hydroxyl-1-adamantyl) amino) acetyl group-2-Cyanopyrolidine; (S)-1-(2-((5-cyanopyridine-2-yl) amino) ethyl-glycyl)-2-Cyanopyrolidine; Isoleucine Thiazolidine (thiazolidide); Isoleucine pyrrolidine (pyrrolidide); With the valine pyrrolidine;
Or its salt or hydrate;
＜6〉according to＜1〉or＜4 pharmaceutical preparation, wherein this inhibitors of dipeptidyl IV is chemical compound or its salt or the hydrate of following formula representative,
Figure A0382539400121
(wherein,
T 1Contain the monocycle or bicyclo-4-to the 12-element heterocycle base of one or two nitrogen-atoms in the representative ring, it can have one or more substituent groups;
The X representative can have one or more substituent C 1-6Alkyl, can have one or more substituent C 2-6Alkenyl, can have one or more substituent C 2-6Alkynyl, can have one or more substituent C 6-10Aryl, can have one or more substituent 5 to 10-person's heteroaryl, can have one or more substituent C 6-10Aryl C 1-6Alkyl, maybe can have one or more substituent 5 to 10-person's heteroaryl C 1-6Alkyl;
Z 1And Z 2Each represents nitrogen-atoms or formula-CR independently 2The group of=representative;
R 1And R 2Each represents Shi-A independently 0-A 1-A 2Group
(A wherein 0Represent singly-bound or C 1-6Alkylidene, it can have 1-3 substituent group that is selected from the group B that is made up of following substituent group;
A 1Represent group, the formula-group of CO-O-representative, the formula-NR of singly-bound, oxygen atom, sulphur atom, sulfinyl, sulfonyl, carbonyl, formula-O-CO-representative AThe group of-representative, formula-CO-NR AThe group of-representative, formula-NR AThe group of-CO-representative, formula-SO 2-NR AThe group of-representative or formula-NR A-SO 2The group of-representative;
A 2And R AEach represents hydrogen atom, halogen atom, cyano group, C independently 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 6-10Aryl, 5 to 10-person's heteroaryl, 4 to 8-element heterocycle bases, 5 to 10-person's heteroaryl C 1-6Alkyl, C 6-10Aryl C 1-6Alkyl or C 2-7Alkyl-carbonyl;
Yet, A 2And R AEach can have 1-3 substituent group that is selected from the basis set B of following replacement independently:
Work as Z 2Be formula-CR 2During the group of=representative, R 1And R 2Can form 5 jointly encircles to 7-person;
Except following situation: [1] R 1Be hydrogen atom; Z 1Be nitrogen-atoms; And Z 2For-CH=; [2] Z 1Be nitrogen-atoms; And Z 2For-C (OH)=;
＜replace basis set B 〉
Replace basis set B and represent following groups: hydroxyl, sulfydryl, cyano group, nitro, halogen atom, trifluoromethyl, can have one or more substituent C 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 6-10Aryl, 5 is to 10-person's heteroaryl, 4 to 8-element heterocycle bases, C 1-6Alkoxyl, C 1-6Alkylthio group, formula-SO 2-NR B1-R B2The group of representative, formula-NR B1-CO-R B2The group of representative, formula-NR B1-R B2(R wherein B1And R B2Each represents hydrogen atom or C independently 1-6Alkyl) group of representative, formula-CO-R B3(R wherein B3Represent 4 to 8-element heterocycle bases) group, the formula-CO-R of representative B4-R B5The group of representative and formula-CH 2-CO-R B4-R B5The group of representative (R wherein B4Represent singly-bound, oxygen atom or formula-NR B6The group of-representative; R B5And R B6Each represents hydrogen atom, C independently 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 6-10Aryl, 5 is to 10-person's heteroaryl, 4 to 8-element heterocycle C 1-6Alkyl, C 6-10Aryl C 1-6Alkyl or 5 is to 10-person's heteroaryl C 1-6Alkyl));
＜7〉according to＜6〉pharmaceutical preparation, T wherein 1Be piperazine-1-base or 3-amino-piperadine-1-base;
＜8〉according to＜6〉pharmaceutical preparation, T wherein 1Be piperazine-1-base;
＜9〉according to＜6〉to＜8 in any one pharmaceutical preparation, wherein X is 3-methyl-2-butene-1-base group, 2-butyne base, benzyl or 2-chlorphenyl;
＜10〉according to＜6〉to＜8 in any one pharmaceutical preparation, wherein X is 3-methyl-2-butene-1-base group or 2-butyne-1-base;
＜11〉according to＜6〉to＜8 in any one pharmaceutical preparation, wherein X is 2-butyne-1-base;
＜12〉according to＜6〉to＜11 in any one pharmaceutical preparation, wherein,
Z 1It is nitrogen-atoms; With
Z 2Be formula-CR 2The group of=representative
(R wherein 2Such as＜6〉in definition);
＜13〉according to＜6〉to＜11 in any one pharmaceutical preparation, wherein
Z 2It is nitrogen-atoms; With
Z 1Be formula-CR 2The group of=representative
(R wherein 2Such as＜6〉in definition);
＜14〉according to＜6〉to＜13 in any one pharmaceutical preparation, wherein R 1Be methyl, cyano group benzyl, fluoro cyano group benzyl, phenethyl, 2-methoxy ethyl or 4-methoxycarbonyl pyridine-2-base;
＜15〉according to＜6〉to＜13 in any one pharmaceutical preparation, wherein R 1Be methyl or 2-cyano group benzyl;
＜16〉according to＜6〉to＜15 in any one pharmaceutical preparation, wherein R 2Be the group of hydrogen atom, cyano group, methoxyl group, carbamyl phenoxyl or following formula representative:
Or
(A wherein 27Represention oxygen atom, sulphur atom or-NH-; A 28And A 29Each represents hydrogen atom or C independently 1-6Alkyl);
＜17〉according to＜6〉to＜15 in any one pharmaceutical preparation, wherein R 2Be hydrogen atom, cyano group or 2-carbamyl phenoxyl;
＜18〉according to＜6〉pharmaceutical preparation, the chemical compound of its Chinese style (I) representative is to be selected from following one of any chemical compound or its salt or hydrate:
(1) 7-(2-butyne base)-2-cyano group-1-methyl-8-(piperazine-1-yl)-1,7-dihydro purine-6-one;
(2) 3-(2-butyne base)-5-methyl-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone also;
(3) 2-(3-amino piperidine-1-yl)-3-(2-butyne base)-5-methyl-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone also;
(4) 2-[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base oxygen base] benzamide;
(5) 7-(2-butyne base)-1-(2-cyano group benzyl)-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-nitrile; With
(6) 2-[3-(2-butyne base)-4-oxo-2-(piperazine-1-yl)-3, the 4-glyoxalidine is [4,5-d] pyridazine-5-ylmethyl also] benzonitrile;
＜19〉according to＜1〉or＜4 pharmaceutical preparation, wherein this inhibitors of dipeptidyl IV is chemical compound or its salt or the hydrate of following formula representative,
Figure A0382539400143
(T wherein 1, X, R 1And R 2Such as＜6〉in definition);
＜20〉according to＜19〉pharmaceutical preparation, T wherein 1Be piperazine-1-base;
＜21〉according to＜19〉or＜20 pharmaceutical preparation, wherein X is 2-butyne base or 2-chlorphenyl;
＜22〉according to＜19〉or＜20 pharmaceutical preparation, wherein X is the 2-butyne base;
＜23〉according to＜19〉to＜22 in any one pharmaceutical preparation, wherein R 1Group for hydrogen atom, methyl, 2-propynyl, 2-butyne base, cyano methyl, phenethyl, phenoxy group ethyl or following formula representative:
(R wherein 3Representation hydroxy, C 1-6Alkoxyl or phenyl);
＜24〉according to＜19〉to＜23 in any one pharmaceutical preparation, wherein R 2Be hydrogen atom, C 1-6The group of alkyl, ethoxyethyl group, oxolane ylmethyl or following formula representative:
(wherein,
R 4And R 5Be same to each other or different to each other, and represent hydrogen atom independently, methyl or phenyl; With
R 6Representation hydroxy, C 1-6Alkoxyl or phenyl),
Or the group of following formula representative:
Figure A0382539400153
＜25〉according to＜19〉pharmaceutical preparation, the chemical compound of its Chinese style (II) representative is to be selected from following one of any chemical compound or its salt or hydrate:
(1) 7-(2-butyne base)-1,3-dimethyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(2) 7-(2-butyne base)-3-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(3) [7-(2-butyne base)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-yl] methyl acetate;
(4) 7-(2-butyne base)-3-methyl-8-(piperazine-1-yl)-1-(2-propynyl)-3,7-dihydro purine-2,6-diketone;
Two (2-butyne the base)-3-methyl-8-(piperazine-1-yl)-3 of (5) 1,7-, 7-dihydro purine-2,6-diketone;
(6) [7-(2-butyne base)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-yl] acetonitrile;
(7) 7-(2-butyne base)-3-methyl isophthalic acid-[(2-oxo-2-phenyl) ethyl]-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(8) 7-(2-butyne base)-3-ethyl-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(9) [7-(2-butyne base)-1-methyl-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] methyl acetate;
(10) 7-(2-butyne base)-3-(2-tetrahydrofuran base) methyl isophthalic acid-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(11) [7-(2-butyne base)-1-methyl-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] phenylacetic acid methyl ester;
(12) 7-(2-butyne base)-3-propyl group-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(13) 7-(2-butyne base)-3-(2-oxo-2-phenethyl)-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(14) 2-[7-(2-butyne base)-1-methyl-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] ethyl propionate;
(15) 7-(2-butyne base)-3-(2-ethoxyethyl group)-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(16) 7-(2-butyne base)-3-isopropyl-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(17) 7-(2-butyne base)-3-(3,3-dimethyl-2-oxo butyl)-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(18) 7-(2-butyne base)-1-methyl-3-(2-oxo-pyrrolidine-3-yl)-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(19) 7-(2-butyne base)-3-(2-ethoxyethyl group)-1-(2-oxo-2-phenylethyl)-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(20) [7-(2-butyne base)-2,6-dioxo-1-(2-oxo-2-phenylethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] methyl acetate;
(21) [7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] ethyl acetate;
(22) [7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] acetas;
(23) 7-(2-butyne base)-3-[2-oxo-2-(pyrrolidine-1-yl) ethyl]-1-(2-phenethyl)-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(24) 2-[7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl]-the N-methylacetamide;
(25) 2-[7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl]-N-cyclopropyl acetamide;
(26) 2-[7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl]-the N-phenyl acetamide; With
(27) 2-[7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl]-N-(2-propynyl) acetamide;
＜26〉according to＜1〉pharmaceutical preparation, wherein this biguanide reagent is metformin;
＜27〉according to＜1〉or＜2 pharmaceutical preparation, it is the medicine of the disease that active form GLP-2 is relevant in active form GLP-1 in prevention or treatment and the blood and/or the blood;
＜28〉according to＜27〉pharmaceutical preparation, wherein this disease be selected from following one of any at least: diabetes, obesity, hyperlipemia and gastrointestinal disease;
＜29〉according to＜3〉or＜4 pharmaceutical preparation, it is the medicine of prevention or the treatment disease relevant with active form GLP-2 in the blood;
＜30〉according to＜29〉pharmaceutical preparation, wherein this disease is a gastrointestinal disease;
＜31〉a kind ofly be used for preventing or the method for the disease that treatment is relevant with active form GLP-2 in blood active form GLP-1 and/or the blood, described method comprise with effective dose give according to＜1 or＜2 pharmaceutical preparation;
＜32〉according to＜1〉or＜2 pharmaceutical preparation preparation be used for preventing or the medicine of the disease that treatment is relevant with active form GLP-2 in blood active form GLP-1 and/or the blood in purposes;
＜33〉a kind ofly be used for preventing or the method for the disease that treatment is relevant with blood active form GLP-2, described method comprise with effective dose give according to＜3 or＜4 pharmaceutical preparation;
＜34〉according to＜3〉or＜4 pharmaceutical preparation preparation be used for preventing or the medicine of the disease that treatment is relevant with blood active form GLP-2 in purposes;
＜35〉a kind of method that is used for strengthening active form GLP-2 effect in blood active form GLP-1 and/or the blood, described method comprise to be used according to＜1〉or＜2 pharmaceutical preparation; With
＜36〉a kind of method that is used for strengthening blood active form GLP-2 effect, described method comprise to be used according to＜3〉or＜4 pharmaceutical preparation.
The present invention also comprises:
＜37〉be used for strengthening the medicine of the effect of active form glucagon-like-peptide-2 (GLP-2) in blood active form glucagon-like-peptide-1 (GLP-1) and/or the blood, it comprises and with inhibitors of dipeptidyl IV and biguanide reagent;
＜38〉be used for strengthening the medicine of the effect of blood active form glucagon-like-peptide-2 (GLP-2), it comprises the biguanide reagent as active component;
＜39〉be used for strengthening the medicine of the effect of blood active form glucagon-like-peptide-2 (GLP-2), it comprises and with inhibitors of dipeptidyl IV and biguanide reagent;
＜40〉medicine of a kind of prevention or treatment diabetes, obesity, hyperlipemia or gastrointestinal disease, it can strengthen the effect of active form glucagon-like-peptide-1 (GLP-1) in the blood, and it comprises inhibitors of dipeptidyl IV and biguanide reagent as active component;
＜41〉medicine of a kind of prevention or treatment gastrointestinal disease, it can strengthen the effect of active form glucagon-like-peptide-2 (GLP-2) in the blood, and it comprises inhibitors of dipeptidyl IV and biguanide reagent as active component; With
＜42〉medicine of a kind of prevention or treatment diabetes, obesity, hyperlipemia or gastrointestinal disease, it comprises as the inhibitors of dipeptidyl IV of active component and biguanide reagent.
＜37 to＜42, preferred as listed above＜5〉to＜25 in any one defined inhibitors of dipeptidyl IV, and biguanide reagent as above＜26 in define.
The specific embodiment
Herein, for convenience of explanation, the structural formula of chemical compound has a certain definite isomer of interval scale.Yet, chemical compound of the present invention can comprise all possible isomer, the optical isomer, stereoisomer, tautomer and the mixture of isomers that cause as geometric isomer possible on the structure, owing to the existence of asymmetric carbon atom, be not limited in order to be convenient to illustrate the isomer of used formula, and can be any one or two kinds of mixture of isomers in two kinds of isomers.Therefore, chemical compound of the present invention can be any one in the Photoactive compounds that has asymmetric carbon atom in their molecule or their racemic compound, be not limited in them but comprise them both.In addition, chemical compound of the present invention can show the crystal polymorphism, but same be not limited to some in these and can be any one in these crystal forms or exist with the form of mixtures of two or more crystal forms.Chemical compound of the present invention also comprises anhydrous and hydrated form.The compounds of this invention is also included within the scope of this claim by the material that the body intracellular metabolic is produced.
Used term and symbol in the definition literary composition, and be described in more detail below the present invention.
Phrase " C as used herein 1-6Alkyl " refer to the alkyl of the straight or branched that contains 1-6 carbon atom; and it is for can be by removing the monoradical that any hydrogen atom obtains from the aliphatic hydrocarbon that contains 1-6 carbon; and especially; comprise for example methyl; ethyl; the 1-propyl group, the 2-propyl group, 2-methyl isophthalic acid-propyl group, 2-methyl-2-propyl group, the 1-butyl, the 2-butyl, the 1-amyl group, the 2-amyl group, the 3-amyl group, the 2-methyl-1-butene base, 3-methyl isophthalic acid-butyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl group, the 1-hexyl, the 2-hexyl, the 3-hexyl, 2-methyl-1-pentene base, 3-methyl-1-pentene base, 4-methyl-1-pentene base, 2-methyl-2-amyl group, 3-methyl-2-amyl group, 4-methyl-2-amyl group, 2-methyl-3-amyl group, 3-methyl-3-amyl group, 2,3-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2,2-dimethyl-1-butyl, 2-ethyl-1-butyl, 3,3-dimethyl-2-butyl and 2,3-dimethyl-2-butyl.
Phrase " C as used herein 2-6Alkenyl " refer to the alkenyl of the straight or branched that contains 2-6 carbon, and especially, comprise for example vinyl, pi-allyl, 1-acrylic, 2-acrylic, 1-butylene base, crotyl, 3-cyclobutenyl, pentenyl and hexenyl.
Phrase " C as used herein 2-6Alkynyl " refer to the alkynyl of the straight or branched that contains 2-6 carbon, and especially, comprise for example acetenyl, 1-propinyl, 2-propynyl, butynyl, pentynyl and hexin base.
Phrase " C as used herein 3-8Cycloalkyl " refer to the annular aliphatic hydrocarbyl group that contains 3-8 carbon atom, and especially, comprise for example cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and ring octyl group.
Phrase " C as used herein 1-6Alkylidene " refer to by " C as defined above 1-6Alkyl " in remove another divalent group that hydrogen atom obtained arbitrarily, and especially, comprise for example methylene, ethylene, 1,1-ethylidene, trimethylene, tetramethylene, pentamethylene and hexamethylene.
Phrase " C as used herein 3-8The ring alkylidene " refer to by " C as defined above 3-8Cycloalkyl " in remove another divalent group that hydrogen atom obtained arbitrarily.
Phrase " C as used herein 1-6Alkoxyl " refer to oxo base and " C as defined above 1-6Alkyl " link to each other; and especially; comprise for example methoxyl group; ethyoxyl; the 1-propoxyl group; the 2-propoxyl group, 2-methyl isophthalic acid-propoxyl group, 2-methyl-2-propoxyl group, the 1-butoxy, the 2-butoxy, the 1-amoxy, the 2-amoxy, the 3-amoxy, 2-methyl-1-butene oxygen base, 3-methyl isophthalic acid-butoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 2,2-dimethyl-1-propoxyl group, the 1-hexyloxy, the 2-hexyloxy, the 3-hexyloxy, 2-methyl-1-pentene oxygen base, 3-methyl-1-pentene oxygen base, 4-methyl-1-pentene oxygen base, 2-methyl-2-amoxy, 3-methyl-2-amoxy, 4-methyl-2-amoxy, 2-methyl-3-amoxy, 3-methyl-3-amoxy, 2,3-dimethyl-1-butoxy, 3,3-dimethyl-1-butoxy, 2,2-dimethyl-1-butoxy, 2-ethyl-1-butoxy, 3,3-dimethyl-2-butoxy and 2,3-dimethyl-2-butoxy.
Phrase " C as used herein 1-6Alkylthio group " refer to thio group and " C as defined above 1-6Alkyl " link to each other, and especially, comprise for example methyl mercapto, ethylmercapto group, 1-rosickyite base, 2-rosickyite base, butylthio and penta sulfenyl.
Phrase " C as used herein 2-7Alkoxy carbonyl " refer to carbonyl and " C as defined above 1-6Alkoxyl " link to each other, and especially, comprise for example methoxycarbonyl, ethoxy carbonyl, 1-propoxycarbonyl and 2-propoxycarbonyl.
Phrase " C as used herein 2-7Alkyl-carbonyl " refer to carbonyl and " C as defined above 1-6Alkyl " link to each other, and especially, comprise for example methyl carbonyl, ethyl carbonyl, 1-propyl group carbonyl and 2-propyl group carbonyl.
Term as used herein " halogen atom " refers to fluorine atom, chlorine atom, bromine atoms or iodine atom.
Phrase " C as used herein 6-10Aryl " refer to the aromatic rings alkyl that contains 6-10 carbon atom, and especially, comprise for example phenyl, 1-naphthyl and 2-naphthyl.
Term as used herein " hetero atom " refers to sulphur atom, oxygen atom or nitrogen-atoms.
Phrase as used herein " 5 to 1O-person's hetero-aromatic ring " refers to and contains one or more heteroatomic fragrant 5 and encircle to 10-person, and especially, comprise for example pyridine ring, thiphene ring, furan nucleus, pyrrole ring oxazole ring isoxazole ring, thiazole ring, thiadiazoles ring (thiadiazole ring), the isothiazole ring, imidazole ring, triazole ring, the pyrazoles ring, the furazan ring, thiadiazoles ring oxadiazole ring, the pyridazine ring, pyrimidine ring, the pyrazine ring, triazine ring, indole ring, the iso-indoles ring, the indazole ring, the chromene ring, the quinoline ring, the isoquinolin ring, the cinnolines ring, quinazoline ring 1,4-Benzodiazine ring, the naphthyridines ring, the 2 ring, purine ring, pteridine ring, the thienofuran ring, the Imidazothiazole ring, the benzofuran ring, benzothiophene ring benzoxazole ring, the benzothiazole ring, the diazosulfide ring, the benzimidazole ring, the imidazopyridine ring, the pyrrolopyridine ring, pyrrolopyrimidine ring and Pyridopyrimidine ring.Preferably " 5 to 10-person's hetero-aromatic ring " comprises pyridine ring, thiphene ring, furan nucleus, pyrrole ring, imidazole ring, 1,2,4-triazole ring, thiazole ring, thiadiazoles ring, pyrazoles ring, furazan ring, thiadiazoles ring, pyridazine ring, pyrimidine ring, pyrazine ring, isoquinolin ring, benzoxazole ring, benzothiazole ring and benzimidazole ring.Most preferred example is a pyridine ring.
Phrase as used herein " 5 to 10-person's heteroaryl " refers to by removing any one or two resulting monovalencies of hydrogen atom or divalent group in above-mentioned " 5 to 10-person's hetero-aromatic ring ".
Phrase as used herein " 4 to 8-element heterocycle " refers to non-aromatic ring, wherein:
(i) atomic number that constitutes this ring is 4-8;
The atom that (ii) constitutes this ring comprises 1-2 hetero atom;
(iii) this ring can contain 1-2 two key;
(iv) this ring can contain 1-3 carbonyl; With
(v) this encircles and is monocycle.
Particularly, described 4 to 8-element heterocycles comprise, for example the ring of one of azetidine ring, pyrrolidine ring, piperidine ring, azepan ring, Azacyclooctane (azocane) ring, oxolane ring, amylene oxide ring, morpholine ring, tetrahydro-1,4-thiazine ring, piperazine ring, Thiazolidine ring, diox ring, imidazoline ring, thiazoline ring and following formula representative:
Figure A0382539400211
Or
Figure A0382539400212
(wherein s represents the integer of 1-3; T 3xRepresent methylene, oxygen atom or formula-NT 4xThe group of-representative, wherein T 4xRepresent hydrogen atom or C 1-6Alkyl.Preferably " 4-to 8-element heterocycle " comprises pyrrolidine ring, piperidine ring, azepan ring, morpholine ring, tetrahydro-1,4-thiazine ring, piperazine ring, dihydrofuran-2-ketone ring and Thiazolidine ring.
Phrase as used herein " 4 to 8-element heterocycle base " refers to by removing any one or two resulting monovalencies of hydrogen atom or divalent group in above-mentioned " 4 to 8-element heterocycle ".Preferably, should " 4 to 8-element heterocycle base " comprise piperidines-1-base, pyrrolidine-1-base and morpholine-4-base.
Phrase " C as used herein 6-10Aryl C 1-6Alkyl " refer to " C as defined above 1-6Alkyl " in any hydrogen atom by " C as defined above 6-10Aryl " replace and the group that obtains, and especially, comprise for example benzyl, phenethyl and 3-phenyl-1-propyl group.
" 5 to 10-person's heteroaryl C for phrase as used herein 1-6Alkyl " refer to " C as defined above 1-6Alkyl " in any hydrogen atom replaced by " 5 to 10-person's heteroaryl " as defined above and the group that obtains, and especially, comprise for example 2-pyridylmethyl and 2-thienyl methyl group.
" 4 to the 8-element heterocycle C of phrase as used herein 1-6Alkyl " refer to " C as defined above 1-6Alkyl " in any hydrogen atom replaced by " 4 to 8-element heterocycle base " as defined above and the group that obtains.
Phrase as used herein " contain the monocycle or bicyclo-4 to the 12-element heterocycle bases of one or two nitrogen-atoms in the ring, it can have one or more substituent groups " refers to it and can have one or more substituent non-aromatic ring groups.In described non-aromatic ring group:
(i) the annular atoms number that constitutes this cyclic group is 4-12;
The annular atoms that (ii) constitutes this cyclic group comprises one or two nitrogen-atoms; With
(iii) this group is monocycle or two ring structures.
Especially, this group is represented by following formula:
Figure A0382539400221
Or
(wherein n and m each represent 0 or 1 independently; R 31To R 44Represent hydrogen atom independently or be selected from substituent group related in the phrase " it can have one or more substituent groups " (as the basis set S of the replacement of giving a definition); R 31To R 44In any two can form C jointly 1-6Alkylidene).
Phrase as used herein " it can have one or more substituent groups " refers in commutable position can have one or more substituent groups with any combination.Especially, this substituent group comprises, for example is selected from the substituent group as the basis set S of replacement that gives a definition.
＜replace basis set S 〉
This group comprises:
(1) halogen atom,
(2) hydroxyl,
(3) sulfydryl,
(4) nitro,
(5) cyano group,
(6) formoxyl,
(7) carboxyl,
(8) trifluoromethyl,
(9) trifluoromethoxy,
(10) amino,
(11) oxo base,
(12) imino group and
(13) formula-T 1x-T 2xThe group of representative (T wherein 1xBe singly-bound, C 1-6The group of alkylidene, oxygen atom, formula-CO-representative, the group of formula-S-representative, the group of formula-S (O)-representative, formula-S (O) 2The group of the group of-representative, formula-O-CO-representative, the formula-group of CO-O-representative, formula-NR TThe group of-representative, formula-CO-NR TThe group of-representative, formula-NR TThe group of-CO-representative, formula-SO 2-NR TThe group of-representative, formula-NR T-SO 2The group of-representative, formula-NH-CO-NR TThe group of-representative or formula-NH-CS-NR TThe group of-representative;
T 2xRepresent hydrogen atom, C 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Alkenyl, C 2-6Alkynyl, phenyl, 1-naphthyl, 2-naphthyl, 5 are to 10-person's heteroaryl or 4 to 8-element heterocycle bases;
R TRepresent hydrogen atom, C 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Alkenyl or C 2-6Alkynyl;
Condition is T 2xAnd R TEach can have 1-3 substituent group that is selected from as the basis set T of replacement that gives a definition independently).
＜replace basis set T 〉
This group comprises: hydroxyl, cyano group, halogen atom, C 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Alkenyl, C 2-6Alkynyl, phenyl, 1-naphthyl, 2-naphthyl, 5 are to 10-person's heteroaryl, 4 to 8-element heterocycles, C 1-6Alkoxyl, C 1-6Alkylthio group, C 2-7Alkoxy carbonyl etc.
＜replace basis set S〉preferably include:
(1) halogen atom,
(2) hydroxyl,
(3) cyano group,
(4) carboxyl,
(5) trifluoromethyl,
(6) trifluoromethoxy,
(7) amino,
(8) C 1-6Alkyl,
(9) C 3-8Cycloalkyl,
(10) C 2-6Alkenyl,
(11) C 2-6Alkynyl,
(12) phenyl and
(13) C 1-6Alkoxyl.
The phrase in replacing basis set B as defined above as used herein " can have one or more substituent C 1-6Alkyl " refer to " C 1-6Alkyl ", it can have the one or more related substituent groups in the phrase " it can have one or more substituent groups " that are selected from commutable position.Preferably, described " can have one or more substituent C 1-6Alkyl " refer to and can have one or two substituent C 1-6Alkyl, this substituent group is selected from cyano group, carboxyl, C 2-7Alkoxy carbonyl, formula-NR 3TCOR 4TThe group of representative, formula-CONR 3TR 4TThe group of representative (R wherein 3TAnd R 4TEach represents hydrogen atom or C independently 1-6Alkyl) and C 1-6Alkoxyl.
In above-mentioned formula (I), phrase " is worked as Z 2Represent Shi-CR 2During the group of=representative, R 1And R 2Can form 5 jointly to 7-person ring " chemical compound that refers to above-mentioned formula (I) representative comprises the chemical compound (II) of following formula representative:
Figure A0382539400241
(Z wherein 1, X and T 1As defined above; A T1Represention oxygen atom, sulphur atom, sulfinyl, sulfonyl, carbonyl, can have one or more substituent methylene, maybe can have one or more substituent nitrogen-atoms; A T2Representative can have one or more substituent C 2-6Alkylidene).In above-mentioned formula (II), A T1Preferred represention oxygen atom, and A T2The preferred C that represents 2-4Alkylidene.
Phrase as used herein " cyano group benzyl " refers to the benzyl with a cyano group, and especially, comprises for example 2-cyano group benzyl, 3-cyano group benzyl and 4-cyano group benzyl.
Phrase as used herein " fluorine cyano group benzyl " refers to the benzyl with a fluorine atom and a cyano group, and especially, comprises for example 2-cyano group-4-luorobenzyl and 2-cyano group-6-luorobenzyl.
Phrase as used herein " carbamyl phenoxyl group " refers to has formula-CONH 2The phenoxy group group of the group of representative, and especially, comprise for example 2-carbamyl phenoxyl group, 3-carbamyl phenoxyl group and 4-carbamyl phenoxyl group.
Phrase as used herein " phenyl oxygen base " and " phenoxy group " are equal to.
In the text without limits, for the type of " salt " if this salt be pharmaceutically acceptable and obtain by any compound deriving of the present invention.This salt comprises, for example inorganic acid salt, acylate, inorganic base salts, organic alkali salt and acidity or alkaline amino acid salt.
The example of preferred inorganic acid salt comprises hydrochlorate, hydrobromate, sulfate, nitrate and phosphate.The example of preferred acylate comprises acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, mesylate and tosilate.
The example of preferred inorganic base salts comprises: alkali metal salt such as sodium salt and potassium salt; Alkali salt such as calcium salt and magnesium salt; Aluminum salt; And ammonium salt.The example of preferred organic alkali salt comprises diethyl amine salt, diethanolamine salt, meglumine salt and N, N '-dibenzyl ethylenediamine salt.
The example of preferred acidic amino acid salt comprises aspartate and glutamate, Glu.The example of preferred alkaline amino acid salt comprises arginine salt, lysinate and ornithine salt.
Term as used herein " effect of active form GLP-2 in active form GLP-1 and/or the blood in the enhancing blood " refers to because the blood levels of these peptides increases, strengthened the effect of active form GLP-2 in active form GLP-1 in the blood and/or the blood, the blood levels increase is because their secretion promotes or decomposes and suppress to cause.
Term as used herein " strengthens the effect of active form GLP-2 in the blood " and refers to because the blood levels of this peptide increases, and has strengthened the effect of active form GLP-2 in the blood, and the blood levels increase is because its secretion promotes or decomposes and suppress to cause.
The effect of active form GLP-1 comprises in the blood: the mode with glucose-dependence improves secretion of insulin; Improve the biosynthesis of insulin; The secretion of glucagon suppression; Promote the β cell to upgrade; Activate the glycogen synthetase in the liver; Inhibition is ingested; Suppress weight increase; Suppress gastric emptying; Secrete with gastric acid inhibitory.
The effect of active form GLP-2 comprises in the blood: promote the epithelial growth of enteral; Promote epithelial growth in the gastrointestinal tract; Suppress epithelial apoptosis in the gastrointestinal tract; Keep gastrointestinal barrier (barrier) function; Improve glucose absorption; The secretion of gastric acid inhibitory; And the blood flow in the raising gastrointestinal tract.
Term " potentiation " refers to and strengthens above-mentioned effect.
As used herein " biguanide reagent " refers to for example phenformin, metformin and buformin, and it is the medicine with following effect: suppress glyconeogenesis and glycogenolysis in the liver; Promote the sensitivity of skeletal muscle to insulin; Suppress the absorption of glucose in the intestinal; Reduce body weight with ingesting by inhibition.Preferred biguanide reagent is metformin.
In the literary composition, " with the relevant disease of active form GLP-2 in active form GLP-1 and/or the blood in the blood " comprises for example diabetes, obesity, hyperlipemia, hypertension, arteriosclerosis and gastrointestinal disease.
In the literary composition, " with the relevant disease of active form GLP-2 in the blood " comprises for example gastrointestinal disease.
Term as used herein " and/or " refer to " with " and " or ".
Can prepare (S)-1-((3-hydroxyl-1-adamantyl) amino) acetyl group-2-Cyanopyrolidine by the method described in the U.S. Patent number 6166063.Can prepare (S)-1-(2-((5-cyanopyridine-2-yl) amino) ethyl-glycyl)-2-Cyanopyrolidine by the method described in the U.S. Patent number 6011155.
Isoleucine Thiazolidine, isoleucine pyrrolidine and valine pyrrolidine can prepare according to the method described in the U.S. Patent number 6548481.
The chemical compound of the formula of pointing out in the literary composition (II) representative can prepare by any method described in the method described in following [typical synthetic method] or U.S. Patent Application Publication No. 2002/0161001, U.S. Patent Application Publication No. 2003/0105077 and the U.S. Patent Application Publication No. 2002/0198205.
[typical synthetic method]
Be used to prepare following formula (I) and (II) exemplary process of the The compounds of this invention of representative be described below.
Each symbol definition in the preparation method is as follows.R 31To R 42, n, m, R 1, R 2, X, A 0, A 1, A 2, R AAnd T 1As defined above.
U 1, U 3Each represents leaving group independently with Hal, as chlorine atom, bromine atoms, iodine atom, mesyloxy or tolysulfonyl oxygen base.
R P1, R P2And R P3Each is represented-the NH-protecting group independently, as oxy acid methyl neopentyl and TMS ethoxyl methyl.
R P4Representation hydroxy-protecting group is as t-butyldimethylsilyl and t-butyldiphenylsilyl.
R P5Represent the NH-protecting group, as N, N-dimethylamino sulfonyl, trityl, benzyl and tert-butoxycarbonyl.
U 2And U 4Each represents chlorine atom, bromine atoms, iodine atom, mesyloxy, tolysulfonyl oxygen base, formula-B (OH) independently 2The group of representative, 4,4,5,5-tetramethyl-1,3,2-two oxa-s monoborane-2-base or formula-Sn (R z) 3(R wherein zRepresent C 1-6Alkyl) group of representative.
R X2Be formula-O-A 2The group of representative, formula-S-A 2The group of representative, formula-N (R A) A 2The group of representative, maybe can have one or more substituent 4-to 8-element heterocycle bases (for example 1-pyrrolidinyl, 1-morpholinyl, 1-piperazinyl or piperidino) etc.
R X3Represent Shi-A 0-A 1-A 2The group of representative is as cyano group, can have one or more substituent C 1-6Alkyl, can have one or more substituent C 3-8Cycloalkyl, can have one or more substituent C 2-6Alkenyl, can have one or more substituent C 2-6Alkynyl and can have one or more substituent C 6-10Aryl.
A 2COORRepresent C 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 6-10Aryl, 5-to 10-member heteroaryl, 4-to 8-element heterocycle base, 5-to 10-member heteroaryl C 1-6Alkyl or C 6-10Aryl C 1-6Alkyl, wherein each contains ester group.
A 2COOHRepresent C 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 6-10Aryl, 5-to 10-member heteroaryl, 4-to 8-element heterocycle base, 5-to 10-member heteroaryl C 1-6Alkyl or C 6-10Aryl C 1-6Alkyl, wherein each contains carboxylic acid.
A 2NO2Represent C 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 6-10Aryl, 5-to 10-member heteroaryl, 4-to 8-element heterocycle base, 5-to 10-member heteroaryl C 1-6Alkyl or C 6-10Aryl C 1-6Alkyl, wherein each contains nitro.
A 2NH2Represent C 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 6-10Aryl, 5-to 10-member heteroaryl, 4-to 8-element heterocycle base, 5-to 10-member heteroaryl C 1-6Alkyl or C 6-10Aryl C 1-6Alkyl, wherein each contains amino.
A 2CNRepresent C 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 6-10Aryl, 5-to 10-member heteroaryl, 4-to 8-element heterocycle base, 5-to 10-member heteroaryl C 1-6Alkyl or C 6-10Aryl C 1-6Alkyl, wherein each contains itrile group.
A CONH2Represent C 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 6-10Aryl, 5-to 10-member heteroaryl, 4-to 8-element heterocycle base, 5-to 10-member heteroaryl C 1-6Alkyl or C 6-10Aryl C 1-6Alkyl, wherein each contains carboxamide groups.
M representative-MgCl ,-MgBr ,-Sn (R z) 3(R wherein zDefine the same) etc.
Term " room temperature " refers to about 20 to about 30 ℃ temperature.
T 1aBe defined as T 1The group of the group of representative or following formula representative:
Figure A0382539400271
The group of following formula representative:
Figure A0382539400272
(R wherein 31To R 44As defined above, except R 31To R 44In any one representative-NH-R P3In addition) or the group of following formula representative:
(R wherein 31To R 40As defined above, except R 31To R 40In any one representative-NH-R P3In addition).
S represents 1-4.
R 51To R 54Each represents hydrogen atom, C independently 1-6Alkyl or C 6-10Aryl.
In the example by the reaction of following reaction scheme representative, unless otherwise indicated, employed reactant, catalyst and other amount (equivalent, weight % and weight ratio) are represented with the ratio to main compound in each reaction scheme.Main compound refers in reaction scheme by the chemical formula representative and has the chemical compound of The compounds of this invention skeleton.
Preparation method A
Figure A0382539400291
[steps A 1]
In this step, general-NH-protection reagent and chemical compound (1a) [CAS No.56160-64-6] reaction obtain chemical compound (2a).Reaction condition is selected according to the type of used-NH-protection reagent.This reaction can be carried out using reagent to introduce under the common used condition of protecting group.
-NH-protection reagent can be to be generally used for introducing-reagent of NH-protecting group.Especially, this-NH-protection reagent comprises for example chloromethyl pivalate.The preferred normal protection reagent of 1-2 that uses.The solvent that is used for this reaction comprises acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, 1,4-diox, oxolane and dimethoxy-ethane.Preferred N, the dinethylformamide of using.
This reaction can be finished in the presence of alkali.The example of used alkali comprises cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate and sodium hydride in this reaction.The preferred sodium hydride that uses.In this case, the use amount of alkali is preferably 1 to 5 equivalent.This reaction can be carried out in 0 ℃-150 ℃ temperature range.Preferred reaction temperature is a room temperature.
[steps A 2]
In this step,, obtain chemical compound (3a) with chemical compound (2a) and chemical compound (2a-2) reaction.
Chemical compound (2a-2) can be any for the chemical compound of electrophilic reagent, as alkyl halide.Instantiation comprises haloalkyl such as iodomethane, iodoethane, iodopropane and benzyl bromide a-bromotoluene; Alkenyl halide such as allyl bromide, bromoallylene and 1-bromo-3-methyl-2-butene; And alkynyl halogenide such as propargyl bromide and 1-bromo-2-butyne.Preferred one to the two normal electrophilic reagent that uses.
The solvent that is used for this reaction comprises, for example dimethyl sulfoxine, N, dinethylformamide, N-Methyl pyrrolidone, diox, oxolane and toluene.
This reaction can be with or without alkali in the presence of finish.The example of used alkali comprises Lithium hydrate, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, hydrofining, butyl lithium, lithium methide, two (TMS) lithium amide, two (TMS) sodium amide and two (TMS) amination potassium in this reaction.In this case, preferably use one to two normal alkali.This reaction can be carried out in 0 ℃-150 ℃ temperature range.
[steps A 3]
In this step, remove the benzyl on chemical compound (3a) the 7-position, obtain chemical compound (4a).
Especially, chemical compound (4a) can prepare by catalytic reduction in the presence of metallic catalyst, but reaction condition be not limited thereto by chemical compound (3a) for example under hydrogen.
The concrete solvent that is used for this reaction comprises, for example methanol, ethanol, propanol, acetic acid, dimethyl sulfoxine, N, dinethylformamide, N-Methyl pyrrolidone, diox, oxolane and toluene.The example of metallic catalyst comprises palladium carbon, platinum oxide and Raney Ni.Metallic catalyst preferably uses with the amount of 0.5-50 weight %.The pressure of hydrogen is preferably 1-5atm.This reaction can be carried out in 0 ℃-150 ℃ temperature range.
[steps A 4]
In this step,, obtain chemical compound (5a) with chemical compound (4a) and chemical compound (4a-2) reaction.
The instantiation of chemical compound (4a-2) is: haloalkyl such as iodomethane, iodoethane, iodopropane and benzyl bromide a-bromotoluene; Alkenyl halide such as allyl bromide, bromoallylene and 1-bromo-3-methyl-2-butene; Or alkynyl halogenide such as propargyl bromide and 1-bromo-2-butyne.These halogenide preferably use with one to two equivalent.
The solvent that is used for this reaction comprises dimethyl sulfoxine, N, dinethylformamide, N-Methyl pyrrolidone, diox, oxolane and toluene.
This reaction can be carried out being with or without under the condition of alkali.The example of used alkali comprises Lithium hydrate, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, hydrofining, butyl lithium, lithium methide, two (TMS) lithium amide, two (TMS) sodium amide and two (TMS) amination potassium in this reaction.In this case, preferably use the normal alkali of 1-4.This reaction can be carried out in 0 ℃-150 ℃ temperature range.
Chemical compound (5a) can obtain with chemical compound (4a-2) prepared in reaction in the presence of copper catalyst and alkali by making chemical compound (4a).In this case, preferably use normal copper catalyst of 0.1-2 and the normal alkali of 1-10.
In this reaction, chemical compound (4a-2) can be aryl boric acid, heteroaryl boric acid etc., and wherein X can have one or more substituent C 6-10Aryl, maybe can have one or more substituent 5-to 10-member heteroaryls, and U 2For-B (OH) 2Deng.Preferred one to the three normal chemical compound (4a-2) that uses.
In this case, reaction dissolvent comprises dichloromethane, chloroform, 1,4-diox, oxolane, toluene, pyridine, N, dinethylformamide and N-Methyl pyrrolidone.
Alkali comprises triethylamine, diisopropylethylamine, pyridine and N, the N-dimethyl aminopyridine.Copper catalyst comprises copper acetate (II), trifluoroacetic acid copper (II), copper chloride (II) and Copper diiodide (II).This reaction can be carried out in 0 ℃-150 ℃ temperature range.
[steps A 5]
In this step, chemical compound (5a) and halide reagent reaction obtain chemical compound (6a).
The instantiation of halide reagent comprises, for example N-chloro-succinimide, N-bromine butanimide and N-iodine butanimide.The use amount of halide reagent is preferably the 1-4 equivalent.
The solvent that is used for this reaction comprises acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, 1,4-diox, oxolane and dimethoxy-ethane.This reaction can be carried out in 0 ℃-150 ℃ temperature range.
[steps A 6]
In this step, chemical compound (6a) and chemical compound (7a) reaction obtain chemical compound (8a).In this case, preferably use the normal chemical compound of 1-4 (7a).
This reaction can be for example as oxolane, acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, methanol, ethanol, 1 in the solvent of 4-diox, toluene and dimethylbenzene, or carry out under the condition that does not have solvent to exist.This reaction can be under 0 ℃-200 ℃ temperature, carries out being with or without in the presence of the alkali.The example of alkali comprises triethylamine, potassium carbonate and 1,8-diazabicylo [5,4,0] endecatylene.In this case, preferably use the normal alkali of 1-4.
[steps A 7]
In this step, remove on the 3-position of chemical compound (8a)-the NH-protecting group, obtain chemical compound (9a).According to remove-the type selecting reaction condition of NH-protecting group.This deprotection reaction can carry out under the condition of this protecting group being generally used for.
For example, work as R P2During for oxy acid methyl neopentyl, this reaction can be used alkali such as Feldalat NM, sodium hydride or 1 in the mixed solution of methanol or methanol and oxolane, and 8-diazabicylo [5,4,0]-7-endecatylene carries out under 0-150 ℃ temperature.In this case, preferably use 0.1 to 2 normal alkali.
Perhaps, work as R P2During for the TMS ethoxyl methyl, this reaction can be as acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, 1, in the solvent of 4-diox, oxolane or dimethoxy-ethane, use fluorination reagent such as tetrabutyl ammonium fluoride or cesium fluoride, under 0-150 ℃ temperature, carry out.In this case, preferably use 1 to 5 normal fluorination reagent.
[steps A 8]
In this step, chlorinated compound (9a) obtains chemical compound (10a).
Reaction condition is had no particular limits, and this reaction can be carried out under the standard conditions of chlorination reaction.For example, this reaction can be carried out in as the solvent of phosphorus oxychloride under 0-150 ℃ temperature.In this case, the halide reagent that preferably uses 10-200 by weight doubly to measure.
Work as R P3During for tert-butoxycarbonyl etc., this group is removed under the above-mentioned condition of using chemical compound such as phosphorus oxychloride, should introduce protecting group again.
Condition for this protective reaction has no particular limits.Under the situation of tert-butoxycarbonyl; this reaction can be used-NH-protection reagent such as Bis(tert-butoxycarbonyl)oxide; at solvent such as acetonitrile, N; dinethylformamide, N-Methyl pyrrolidone, 1; in 4-diox, oxolane or the dimethoxy-ethane; in the presence of alkali such as Lithium hydrate, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate or triethylamine, under 0-150 ℃, carry out.
[steps A 9]
In this step, make chemical compound (10a) and chemical compound (11a-2) reaction, obtain chemical compound (11a).
Chemical compound (11a-2) comprises A 2The alcoholic compound of-OH representative or phenolic compounds, A 2(R A) amines etc. of NH representative, and A 2The mercaptan compound of-SH representative.In this case, the consumption of chemical compound (11a-2) is preferably by weight 1-10 equivalent or 5-100 doubly.
The solvent that is used for this reaction comprises acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, 1,4-diox, oxolane, dimethoxy-ethane, methanol and ethanol.
This reaction can be carried out being with or without under the condition of alkali.Used alkali comprises Lithium hydrate, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, hydrofining, butyl lithium, lithium methide, two (TMS) lithium amide, two (TMS) sodium amide, two (TMS) amination potassium and triethylamine in this reaction.In this case, preferably use the normal alkali of 1-10.This reaction can be carried out in 0 ℃-150 ℃ temperature range.
[steps A 10]
In this step, chemical compound (10a) reacts in the presence of metallic catalyst with chemical compound (13a), obtains chemical compound (12a).In this case, preferably use the normal chemical compound of 1-50 (13a).
The solvent that is used for this reaction comprises acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, 1,4-diox, oxolane, dimethoxy-ethane, methanol and ethanol.
Metallic catalyst comprises palladium catalyst and copper catalyst.Palladium catalyst comprises tetrakis triphenylphosphine palladium, palladium and dibenzalacetone (dibenzylidene acetone) palladium.Copper catalyst comprises Copper diiodide.The preferred normal metallic catalyst of 0.01-2 that uses.
This reaction can be carried out in the presence of organophosphor ligand.When carrying out under this is reflected at the existence of organophosphor ligand, the example of this part comprises o-tolyl phosphine and diphenylphosphine ferrocene.In this case, preferably use the normal organophosphor ligand of 1-5 for metallic catalyst.
This reaction can be carried out being with or without under the condition of alkali.Used alkali comprises Lithium hydrate, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, hydrofining, potassium phosphate, two (TMS) lithium amide, two (TMS) sodium amide, two (TMS) amination potassium and triethylamine in this reaction.This reaction can be carried out in 0 ℃-150 ℃ temperature range.
[steps A 11]
In this step, chemical compound (10a) and cyanating reagent reaction obtain chemical compound (14a).
Particularly, cyanating reagent comprises for example Cyanogran. and potassium cyanide.Consumption is preferably the 1-20 equivalent.
The solvent that is used for this reaction comprises, for example acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, 1,4-diox, oxolane, dimethoxy-ethane, methanol and ethanol.This reaction can be carried out in 0 ℃-150 ℃ temperature range.
[steps A 12]
In this step, the cyano group of hydrolysis compound (14a) obtains chemical compound (15a).Reaction condition is had no particular limits, and this reaction can be carried out being generally used for by hydrolysis cyano group being converted under the condition of carbamoyl.
The solvent that is used for this reaction comprises N, dinethylformamide, N-Methyl pyrrolidone, 1, the mixed solvent of 4-diox, oxolane, dimethoxy-ethane, methanol, ethanol and oxolane and methanol.
This reaction can be carried out being with or without under the condition of alkali.When using alkali, can use the aqueous solution of alkali such as potassium hydroxide, sodium hydroxide, Lithium hydrate or ammonia to carry out this reaction.This reaction can be finished after adding aqueous hydrogen peroxide solution (aqueous solution of preferred 30% hydrogen peroxide).
This reaction can be carried out in 0 ℃-150 ℃ temperature range.
[steps A 13]
In this step, remove the R of chemical compound (16a) P3, obtain chemical compound (17a).Chemical compound (11a), (12a), (14a), (15a) and other can be used as chemical compound (16a).
R P3Deprotection reaction can be used to remove-carrying out under the standard reaction condition of NH-protecting group.
For example, work as R P3During for tert-butoxycarbonyl, this reaction can be at the absolute methanol solution of acid as hydrogen chloride, and the ethanol solution of hydrogen chloride carries out under the existence of no Shui dioxane solution of hydrogen chloride, trifluoroacetic acid or formic acid.
Another method of preparation chemical compound (10a) is described below.
[steps A 14]
In this step, chlorinated compound (18a) obtains chemical compound (19a).Reaction condition is had no particular limits, and this reaction can be carried out under the chlorating standard conditions being used for.For example, this reaction can be carried out under 0-150 ℃ temperature in solvent such as phosphorus oxychloride.Preferably use 10-200 chlorination reagent doubly by weight.
Work as R P3During for tert-butoxycarbonyl etc., this group is removed under the above-mentioned condition of using chemical compound such as phosphorus oxychloride, should introduce protecting group again.
Condition to protective reaction has no particular limits, and works as R P3During for tert-butoxycarbonyl; this reaction can be used-NH-protection reagent such as Bis(tert-butoxycarbonyl)oxide; at solvent such as acetonitrile, N; dinethylformamide, N-Methyl pyrrolidone, 1; in 4-diox, oxolane and the dimethoxy-ethane; in the presence of alkali such as Lithium hydrate, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate or triethylamine, under 0-150 ℃, carry out.
[steps A 15]
In this step, chemical compound (19a) is obtained chemical compound (20a) by partial hydrolysis.This is reflected under the existence of alkali such as sodium acetate, potassium carbonate or sodium hydroxide and carries out.Preferably use one to decanormal alkali.The solvent that is used for this reaction comprises dimethyl sulfoxine, N-Methyl pyrrolidone, oxolane, water and its mixture.This reaction can be carried out under 0 ℃-100 ℃ temperature.
[steps A 16]
In this step, chemical compound (20a) and chemical compound (21a) reaction obtain chemical compound (22a).This reaction can with [steps A 2] of preparation method A in carry out under used the same terms.
The another kind of method of preparation chemical compound (19a) is described below.
Figure A0382539400351
[steps A 17]
In this step, use chemical compound (23a) [CASNo.1076-22-8] and chemical compound (4a-2) to carry out substitution reaction, obtain chemical compound (24a).
This reaction can with [steps A 4] of preparation method A in carry out under used the same terms.
[steps A 18]
In this step, chemical compound (24a) and halide reagent reaction obtain chemical compound (25a).
This reaction can with [steps A 5] of preparation method A in carry out under used the same terms.
[steps A 19]
In this step, chlorinated compound (25a) obtains chemical compound (26a).
Reaction condition is had no particular limits, and chemical compound (25a) can with phosphorus oxychloride, phosphorus pentachloride or its mixture, in solvent or do not have under 0-150 ℃ temperature, to react in the presence of the solvent.Solvent for example comprises, toluene, acetonitrile and dichloroethanes.
[steps A 20]
In this step, chemical compound (26a) and chemical compound (7a) reaction obtain chemical compound (19a).This reaction can with [steps A 6] of preparation method A in carry out under used the same terms.
Preparation method B
Figure A0382539400361
[step B1]
In this step, (1b) carries out benzylation with chemical compound, and the cracking sugar chain, obtains chemical compound (2b).
Reaction condition is had no particular limits.Chemical compound (2b) can obtain by following method: make chemical compound (1b) and benzyl bromide a-bromotoluene as acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, dimethyl sulfoxine, 1, in 4-diox, oxolane, dimethoxy-ethane, methanol or the alcoholic acid solvent, under 0-150 ℃ temperature, react, add the normal hydrochloric acid of 3-10, and mixture is incubated (incubating) with the cracking sugar moieties under 0-150 ℃ temperature.The preferred normal benzyl bromide a-bromotoluene of 1-3 that uses.
[step B2]
In this step, chemical compound (2b) and halide reagent reaction obtain chemical compound (3b).This halogenation can with [steps A 5] of preparation method A in carry out under used the same terms.
[step B3]
In this step, chemical compound (3b) and chemical compound (4b) reaction obtain chemical compound (5b).This reaction can with [steps A 6] of preparation method A in carry out under used the same terms.
[step B4]
In this step, chemical compound (5b) and chemical compound (5b-2) reaction obtain chemical compound (6b).This reaction can with [steps A 2] of preparation method A in carry out under used the same terms.
[step B5]
In this step, remove the R of chemical compound (6b) P3, obtain chemical compound (7b).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
Preparation method B-2
The chemical compound of following formula representative (9b) can prepare by following method:
Use H-T 1aThe chemical compound of representative (8b) replaces the chemical compound (7a) in [steps A 6] of preparation method A as mentioned above, with [steps A 6] under the used same reaction conditions, and suitably use aforesaid [steps A 7] then to [steps A 13].
The chemical compound of following formula representative (10b) can prepare by following method:
Use H-T 1aThe chemical compound of representative (8b) replaces the chemical compound (3b) among [the step B3] of preparation method B as mentioned above, with [step B3] under the used same reaction conditions, and suitably use aforesaid [step B4] then to [step B6].The preferred embodiment of chemical compound (8b) comprises piperidines-3-aminocarbamic acid tert-butyl ester.
Preparation method C
[step C1]
In this step, chemical compound (1c) and chemical compound (1c-2) reaction obtain chemical compound (2c).This reaction can with [steps A 4] of preparation method A in carry out under used the same terms.
[step C2]
In this step, chemical compound (1c) and ethanol synthesis obtain chemical compound (3c).
Chemical compound (3c) can be for example, by acid as sulphuric acid or hydrochloric acid in the presence of, the alcoholic solution acquisition of reflux chemical compound (2c).Yet reaction condition is not limited thereto.In this reaction, preferably use one to two normal acid.
[step C3]
In this step, chemical compound (2c) and ethanol synthesis obtain chemical compound (4c) and (5c).This reaction can with preparation method C in [step C2] in carry out under used the same terms.
[step C4]
In this step, the reaction of chemical compound (3c) and chemical compound (3c-2) obtains chemical compound (4c) and (5c).This reaction can with preparation method A in [steps A 4] in carry out under used the same terms.
[step C5]
In this step, chemical compound (4c) and chemical compound (6c) reaction obtain chemical compound (7c).This reaction can with preparation method A in [steps A 6] in carry out under used the same terms.
[step C6]
In this step,, obtain chemical compound (8c) with chemical compound (7c) thioamidesization.The solvent that is used for this reaction comprises methanol, ethanol, N, dinethylformamide, N-Methyl pyrrolidone, 1,4-diox, oxolane and dimethoxy-ethane.Thioamides reagent comprises ammonium sulfide, sodium sulfide and hydrogen sulfide.The preferred normal thioamides reagent of 2-10 that uses.When using hydrogen sulfide as thioamides reagent, this is reflected at alkali such as triethylamine or N, and the N-diisopropylethylamine carries out under existing.This reaction can be carried out in 0 ℃-150 ℃ temperature range.
[step C7]
In this step, chemical compound (8c) and methylating reagent reaction obtain chemical compound (9c).Methylating reagent comprises trimethyl oxygen tetrafluoroborate (trimethyl oxonium tetrafluoroborate), Methylsulfate, iodomethane and trimethyl phosphite.The preferred normal methylating reagent of 1.0-1.5 that uses.
When using trimethyl oxygen tetrafluoroborate as methylating reagent, chemical compound (9c) can carry out this prepared in reaction and obtain by in halogenated solvent such as dichloromethane under 0 ℃ to 50 ℃ temperature.
When using Methylsulfate, iodomethane or trimethyl phosphite as methylating reagent, chemical compound (9c) can carry out this prepared in reaction under the N-diisopropylethylamine exists and obtain by at alkali such as potassium carbonate, triethylamine or N.In this case, preferably use the normal alkali of 1.0-1.5.The solvent that is used for this reaction comprises acetone, N, dinethylformamide, N-Methyl pyrrolidone, 1,4-diox, oxolane and dimethoxy-ethane.This reaction can be finished under 0 ℃-100 ℃ temperature.
[step C8]
In this step, hydrolysis compound (9c) obtains chemical compound (10c).
Reaction condition to hydrolysis has no particular limits.This reaction can be in the mixed solvent of second alcohol and water, acid as sulphuric acid, hydrochloric acid or p-methyl benzenesulfonic acid in the presence of, under 0 ℃-80 ℃ temperature, carry out.In this case, preferably use the normal acid of 5-50.
Work as R P3When being the group as tert-butoxycarbonyl, it is removed under these conditions, should introduce protecting group again.The introducing reaction condition of protecting group has no particular limits hereto.Work as R P3During for tert-butoxycarbonyl, this reaction can use reagent as the two carbonic acid tert-butyl esters, at solvent such as dichloromethane, chloroform, N, in dinethylformamide or the oxolane, at alkali such as pyridine, 4-aminopyridine, triethylamine and N, the N-diisopropylethylamine exists down, carries out under 0 ℃-80 ℃ temperature.In this case, preferably use the normal alkali of 2-3.
[step C9]
In this step, chemical compound (10c) and Reducing agent reaction obtain chemical compound (11c).
Reductive reaction condition is had no particular limits.This reaction can be finished by following method: make chemical compound (10c) and hydrogen in the presence of Raney Ni, at solvent such as benzene, ethanol, the 2-propanol, or in the acetone, under 0 ℃ to 50 ℃ temperature, react, perhaps make chemical compound (10c) and Reducing agent such as sodium borohydride, at solvent such as methanol, ethanol, or 2-methyl-2-propanol, or in the mixed solvent of water and oxolane, under 0 ℃ to 50 ℃ temperature, react, perhaps make chemical compound (10c) and Reducing agent such as sodium borohydride, in the presence of normal mercury salt of 1-5 such as mercuric acetate, at solvent such as methanol, ethanol, or in 2-methyl-2-propanol, under 0 ℃ to 50 ℃ temperature, react.Preferred two to the three normal Reducing agents that use.
[step C10]
In this step, make chemical compound (11c) carry out oxidation reaction, obtain chemical compound (12c).
When using oxidant such as manganese dioxide, pyridinium chlorochromate or dichromic acid pyridine to be used for oxidation reaction, chemical compound (12c) can carry out this prepared in reaction and obtain by in solvent such as dichloromethane or chloroform under 20 ℃-80 ℃ temperature.Perhaps, chemical compound (12c) also can carry out this prepared in reaction and obtains under standard conditions by primary alconol being oxidized to aldehyde such as Swern oxidation.The preferred normal oxidant of 5-20 that uses.
[step C11]
In this step, chemical compound (12c) and chemical compound (13c) reaction obtain chemical compound (17c).In this case, preferably use the normal chemical compound of 2-10 (13c).
Chemical compound (17c) can obtain by following prepared in reaction: for example by making chemical compound (12c) and (13c) at solvent such as methanol, ethanol, 1-Methyl-2-Pyrrolidone, 1, in 4-diox, oxolane or the dimethoxy-ethane, or do not have solvent to have mixing down, and mixture is reacted under 20-150 ℃ temperature.Yet reaction condition is not limited thereto.
[step C12]
In this step, chemical compound (12c) and hydrazine reaction obtain chemical compound (15c).This reaction can with [the step C11] of preparation method C in carry out under used the same terms.The preferred normal hydrazine of 2-10 that uses.
[step C13]
In this step, substitution reaction uses chemical compound (15c) and chemical compound (16c) to finish, and obtains chemical compound (17c).This reaction can with [steps A 2] of preparation method A in carry out under used the same terms.The preferred normal chemical compound of 1-3 (16c) that uses.
[step C14]
In this step, remove the R of chemical compound (17c) P3, obtain chemical compound (14c).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
[step C15]
In this step, chemical compound (5c) and chemical compound (6c) reaction obtain chemical compound (18c).This reaction can with [steps A 6] of preparation method A in carry out under used the same terms.
[step C16]
In this step, hydrolysis compound (18c) obtains chemical compound (19c).
Reaction condition to hydrolysis has no particular limits.For example, chemical compound (19c) can prepare being incubated under 0 ℃-100 ℃ temperature in the presence of the alkali by making chemical compound (18c).
The solvent that is used for this reaction comprises methanol, ethanol, oxolane, water or its mixture.Alkali comprises Lithium hydrate, sodium hydroxide and potassium hydroxide.The preferred normal alkali of 1-2 that uses.
[step C17]
In this step, chemical compound (19c) and Reducing agent reaction obtain chemical compound (20c).This reduction can be finished under the standard conditions that carboxylic acid are reduced to methanol.
Reducing agent comprises borane derivative such as borine-tetrahydrofuran complex and borine methyl thioether complex, and sodium borohydride.The preferred normal Reducing agent of 5-30 that uses.
When using borane derivative as Reducing agent, chemical compound (20c) can be by using solvent as 1, and 4-diox, oxolane or dimethoxy-ethane carry out this prepared in reaction and obtain under-78 ℃-35 ℃ temperature.
Perhaps, when using sodium borohydride, at first make chemical compound (19c) and activator such as isobutyl chlorocarbonate as Reducing agent, under-78 ℃-20 ℃ temperature, react, with Reducing agent such as sodium borohydride, under-78 ℃-35 ℃ temperature, react then, obtain chemical compound (20c).The solvent that is used for this reaction comprises 1,4-diox, oxolane and dimethoxy-ethane.
[step C18]
In this step, thioamides chemical compound (20c) obtains chemical compound (21c).This reaction can with [the step C6] of preparation method C in carry out under used the same terms.
[step C19]
In this step, chemical compound (21c) reacts in the presence of alkali with sillylation reagent, obtains chemical compound (22c).
The solvent that is used for this reaction comprises dichloromethane, N, dinethylformamide, 1,4-diox, oxolane and dimethoxy-ethane.Alkali comprises imidazoles, pyridine, 4-dimethylaminopyridine, triethylamine and N, the N-diisopropylethylamine.Sillylation reagent comprises tert-butyl chloro-silicane and tertiary butyl chloride diphenyl silane.Preferred normal alkali of 1.0-1.5 and the normal sillylation reagent of 1.0-1.5 of using.This reaction can be carried out under 0 ℃-80 ℃ temperature.
[step C20]
In this step, the chemical compound that methylates (22c) obtains chemical compound (23c).
This reaction can with [the step C7] of preparation method C in carry out under used the same terms.
[step C21]
In this step, hydrolysis compound (23c) obtains chemical compound (24c).
Reaction condition to hydrolysis has no particular limits.Chemical compound (24c) can be by in the mixed solvent of second alcohol and water, acid as sulphuric acid, hydrochloric acid or p-methyl benzenesulfonic acid in the presence of, under 50 ℃-100 ℃ temperature, carry out this prepared in reaction and obtain.
When this reaction causes-R P3When removing, protected again by protective reaction-NH-.Especially, for example work as R P3During for tert-butoxycarbonyl, this reaction can use reagent as two dimethyl dicarbonate butyl esters, at solvent such as dichloromethane, chloroform, N, in dinethylformamide or the oxolane, at alkali such as pyridine, 4-aminopyridine, triethylamine or N, the N-diisopropylethylamine exists down, carries out under 0 ℃-80 ℃ temperature.Yet this reaction is not limited thereto.
Preparation method D
[step D1]
In this step, chemical compound (1d) and chemical compound (1d-2) reaction obtain chemical compound (2d).
Especially, chemical compound (1d-2) for example comprises, haloalkyl such as iodomethane, iodoethane, iodopropane, benzyl bromide a-bromotoluene, 2-bromoacetophenone, chloromethyl benzylic ether and bromoacetonitrile; Alkenyl halide such as allyl bromide, bromoallylene and 1-bromo-3-methyl-2-butene; And alkynyl halogenide such as propargyl bromide and 1-bromo-2-butyne.The preferred normal chemical compound of 1-1.5 (1d-2) that uses.
The solvent that is used for this reaction comprises N, dinethylformamide, N-Methyl pyrrolidone, oxolane, 1,2-dimethoxy-ethane, 1,4-diox and dichloromethane.This reaction can be carried out being with or without under the condition of alkali.Alkali used in this reaction comprises 1,8-diazabicylo [5,4,0] endecatylene, triethylamine, N, N-diisopropylethylamine and sodium hydride.In this case, preferably use the normal alkali of 1-1.5.This reaction can be carried out in 0 ℃-150 ℃ temperature range.
[step D2]
In this step, chemical compound (2d) and nitrite reaction obtain chemical compound (3d).
The solvent that is used for this reaction comprises water and is selected from N, dinethylformamide, N-Methyl pyrrolidone, oxolane, 1,2-dimethoxy-ethane and 1, the mixed solvent of 4-diox solvent.Nitrite comprises sodium nitrite and potassium nitrite.The preferred normal nitrite of 3-5 that uses.This reaction can be carried out under 20 ℃ to 120 ℃ temperature.
[step D3]
In this step, chemical compound (3d) and ammonia reaction obtain chemical compound (4d).The preferred normal ammonia of 10-20 that uses.
This reaction can in the 4-diox, be finished under 20 ℃-200 ℃ temperature at solvent such as methanol, ethanol or 1.
[step D4]
In this step, under the hydrogen or in the presence of the normal hydrazine of 2-3, use metallic catalyst to carry out catalytic reduction chemical compound (4d), obtain chemical compound (5d).
The solvent that is used for this reaction comprises methanol, ethanol, N, dinethylformamide, oxolane, 1,2-dimethoxy-ethane, 1,4-diox, water or its mixed solvent.Metallic catalyst comprises palladium carbon, platinum oxide and Raney Ni.Use the amount of metallic catalyst to be preferably 0.5-10 weight %.This reaction can be carried out in 0 ℃-150 ℃ temperature range.
[step D5]
In this step, chemical compound (5d) and orthoformate reaction obtain chemical compound (6d).
This reaction is finished in the presence of carboxylic acid anhydrides such as acetic anhydride.Orthoformate comprises original acid A ester and ethyl orthoformate.The orthoformate and the normal carboxylic acid anhydrides of 3-10 that preferably use 1-20 by weight doubly to measure.This reaction can be carried out under 20 ℃-200 ℃ temperature.
[step D6]
In this step, the NH group on the 1-position of protection chemical compound (6d) obtains chemical compound (7d).
Protection reagent comprises N, N-dimethylamino sulfonyl chlorine, trityl chloride, Bis(tert-butoxycarbonyl)oxide and benzyl bromide a-bromotoluene.The preferred normal protection reagent of 1-1.5 that uses.The solvent that is used for this reaction comprises dichloromethane, chloroform, carbon tetrachloride, toluene, N, dinethylformamide and oxolane.Alkali comprises pyridine, 4-dimethylaminopyridine, 1,8-diazabicylo [5,4,0] endecatylene, triethylamine and N, N-diisopropylethylamine.Under typical situation, preferably use 1.2 normal alkali.Yet, when protection reagent is Bis(tert-butoxycarbonyl)oxide, preferably use the normal 4-dimethylaminopyridine of 0.005-0.1.This reaction can be carried out under 20 ℃-200 ℃ temperature.
[step D7]
In this step, chlorinated compound (7d) obtains chemical compound (8d).
Reaction condition is had no particular limits.For example, this reaction is carried out according to following.Chemical compound (7d) and alkali are reacted under-100 ℃-20 ℃ temperature, and then itself and chlorination reagent are reacted.This reacting generating compound (8d).Chemical compound (8d) also can obtain by making chemical compound (7d) and alkali prepared in reaction in the presence of chlorination reagent.The solvent that is used for this reaction for example comprises, ether, oxolane, 1,2-dimethoxy-ethane and 1,4-diox.Alkali comprises n-BuLi, tert-butyl lithium, diisopropylaminoethyl lithium, two (TMS) lithium amide and diisopropylaminoethyl magnesium.The preferred normal alkali of 1-1.5 that uses.Chlorination reagent comprises hexachlorethane and N-chloro-succinimide.The preferred normal chlorination reagent of 1-3 that uses.
[step D8]
In this step, chemical compound (8d) and chemical compound (9d) reaction obtain chemical compound (10d).This reaction can with [steps A 6] of preparation method A in carry out under used the same terms.
[step D9]
In this step, substitution reaction uses chemical compound (10d) and chemical compound (10d-2) to finish, and obtains chemical compound (11d).This reaction can with [steps A 4] of preparation method A in carry out under used the same terms.
[step D10]
In this step, remove the R of chemical compound (11d) P3, obtain chemical compound (12d).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
[step D11]
In this step, the group on the 5-position of chemical compound (11d) obtains by taking off the alkyl effect, obtains chemical compound (13d).The reaction condition that takes off the alkyl effect is had no particular limits.For example, following reaction condition can be finished this reaction:
Work as R 1When being the benzyloxy methyl,, in solution, under-100 ℃-20 ℃ temperature, react as dichloromethane with chemical compound (11d) and the normal Boron tribromide of 3-10, boron chloride etc.This reacting generating compound (13d).
When this reaction causes removing R P3The time, protect again-NH-by protective reaction.Especially, for example work as R P3When being tert-butoxycarbonyl, this reaction can be used reagent such as Bis(tert-butoxycarbonyl)oxide, at solvent such as dichloromethane, chloroform, N, in dinethylformamide or the oxolane, at alkali such as pyridine, 4-aminopyridine, triethylamine or N, the N-diisopropylethylamine exists down, finishes under 0 ℃-80 ℃ temperature.Yet this reaction is not limited thereto.
[step D12]
In this step, chemical compound (13d) and chemical compound (13d-2) reaction obtain chemical compound (14d).This reaction can with [the step D1] of preparation method D in carry out under used the same terms.
[step D13]
In this step, remove the R of chemical compound (14d) P3, obtain chemical compound (12d).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
Another method for preparing chemical compound (11d) is described below.
Figure A0382539400471
[step D14]
In this step,, obtain chemical compound (15d) with chemical compound (8d) deprotection.
This deprotection reaction can be finished under the standard reaction condition according to the kind of protecting group.For example; under the situation of tert-butoxycarbonyl, this deprotection reaction can be by using alkali such as sodium hydroxide, potassium carbonate and ammonia, at oxolane, N; in dinethylformamide, methanol, ethanol, water or its mixed solvent, under 0 ℃-100 ℃ temperature, carry out this and react and finish.When adding solvent and alkali behind the chlorinating step in front, can under the situation of separating compound (8d) not, finish this deprotection reaction.
[step D15]
In this step, X is incorporated in the chemical compound (15d), obtain chemical compound (16d).This reaction can be used X-U 2, with [steps A 4] of preparation method A in carry out under used the same terms.
Can use the Mitsunobu reaction to introduce alcohol (X-OH).Particularly, chemical compound (16d) can be by making alcohol (X-OH) and azoformic acid dialkyl and triphenylphosphine, and in solvent such as oxolane, prepared in reaction obtains under-70 ℃ of-50 ℃ of temperature.
[step D16]
In this step, chemical compound (16d) and chemical compound (9d) reaction obtain chemical compound (11d).
This reaction can with [steps A 6] of preparation method A in carry out under used the same terms.
Preparation method E
The chemical compound of following formula representative (1e) can prepare by following method:
Figure A0382539400481
Use H-T 1aThe chemical compound of representative (8b) replaces [step C5] or the chemical compound (6c) in [step C15] of above-mentioned preparation method C, with [step C5] under used the same terms, and suitably use aforesaid [step C6] then to [step C21].
The chemical compound of following formula representative (1e) can prepare by following method:
Use H-T 1aThe chemical compound of representative (8b) replaces the chemical compound (9d) among [the step D8] of above-mentioned preparation method D, with [step D8] under the used same reaction conditions, suitably use aforesaid [step D9] then to [step D13].
Preparation method F
Figure A0382539400483
[step F 1]
In this step, the ester group of hydrolysis compound (1f) obtains chemical compound (2f).This reaction can with [the step C16] of preparation method C in carry out under used the same terms.
[step F 2]
In this step, remove the R of chemical compound (2f) P3, obtain chemical compound (3f).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
Preparation method G
[step G1]
In this step, the nitro of reducing compound (1g) obtains chemical compound (2g).
The solvent that is used for this reaction comprises methanol, ethanol, oxolane, water or its mixture.Reducing agent comprises ferrum, stannum and zinc.Catalyst comprises hydrochloric acid and ammonium salt such as ammonium chloride.This reaction can be carried out under 20 ℃ to 120 ℃ temperature.
[step G2]
In this step, remove the R of chemical compound (2g) P3, obtain chemical compound (3g).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
Preparation method H
[step H1]
In this step, the itrile group of hydrolysis compound (1h) obtains chemical compound (2h).
Reaction condition is had no particular limits.For example, this reaction is carried out according to following.Chemical compound (2h) can be by making chemical compound (1h) and hydrogen peroxide, and in the presence of alkali, prepared in reaction obtains under-20 ℃-50 ℃ temperature.Solvent comprises methanol, ethanol, oxolane, water or its solvent mixture.Alkali comprises ammonia and alkylamine such as triethylamine.
[step H2]
In this step, remove the R of chemical compound (2h) P3, obtain chemical compound (3h).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
Preparation method I
[step I1]
In this step,, obtain chemical compound (2i) with chemical compound (1i) and alkylmetal reagent or metal aryl reagent reacting.
Reaction condition is had no particular limits.For example, this reaction is carried out according to following.Chemical compound (1i) and reagent such as lithium alkylide, aryl lithium, alkyl Grignard reagent or aryl grignard reagent in the solvent as ether or oxolane, can be reacted under-100 ℃ to 100 ℃ temperature.Perhaps, this chemical compound can with zinc alkyl or aryl zinc, at solvent such as N, in dinethylformamide or the 1-Methyl-2-Pyrrolidone, under 0 ℃ to 50 ℃ temperature, react.
[step I2]
In this step, oxidized compound (2i) obtains chemical compound (3i).The typical agents that is generally used for oxidation alcohol can be used as oxidant.Especially, for example in solvent such as dichloromethane or chloroform, under 20-100 ℃ temperature, can use manganese dioxide as oxidant.Perhaps, in solvent such as dimethyl sulfoxine, under 20-100 ℃ temperature, can use the sulfur trioxide pyridine as oxidant.Perhaps, can be in solvent such as dichloromethane or chloroform, under-50-50 ℃ temperature, use Dess-Martin periodinane.
[step I3]
In this step, chemical compound (3i) and hydrazine reaction obtain chemical compound (4i).This reaction can with [the step C12] of preparation method C in carry out under used the same terms.
[step I4]
In this step, substitution reaction is to use chemical compound (4i) and chemical compound (5i) to finish, and obtains chemical compound (6i).This reaction can with [steps A 2] of preparation method A in carry out under used the same terms.
[step I5]
In this step, remove the R of chemical compound (6i) P3, obtain chemical compound (7i).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
[step I6]
In this step, remove the R of chemical compound (4i) P3, as the R of chemical compound (7i) 1During for H, obtain chemical compound (7i).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
Preparation method J
Figure A0382539400531
[step J1]
In this step, with chemical compound (1j) and cyanating reagent, reaction obtains chemical compound (2j) in the presence of catalyst.
Cyanating reagent comprises Cyanogran. and potassium cyanide.Catalyst comprises acetic acid.Solvent comprises for example acetonitrile.This reaction can be carried out under 0 ℃-100 ℃ temperature.
[step J2]
In this step, the itrile group of hydrolysis compound (2j) obtains chemical compound (3j).This reaction can with [the step H1] of preparation method H in carry out under used the same terms.
[step J3]
In this step, the hydroxyl of oxidized compound (3j) obtains chemical compound (4j).This reaction can with [the step I2] of preparation method I in carry out under used the same terms.
[step J4]
In this step, chemical compound (4j) and chemical compound (5j) reaction obtain chemical compound (6j).This reaction can with [the step C11] of preparation method C in carry out under used the same terms.
[step J5]
In this step, remove the R of chemical compound (6j) P3, obtain chemical compound (7j).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
[step J6]
In this step, the carbamoyl group of chemical compound (6j) is dewatered in the presence of alkali, obtain chemical compound (8j).
Dehydrant comprises for example phosphorus oxychloride.Alkali comprises alkylamine such as triethylamine.Solvent comprises dichloromethane and chloroform.Perhaps, this reaction can be carried out under the condition of solvent not having.This reaction can be carried out under 0 ℃-100 ℃ temperature.
[step J7]
In this step, remove the R of chemical compound (8j) P3, obtain chemical compound (9j).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
Preparation method K
Figure A0382539400551
[step K 1]
In this step, use chemical compound (1k) and chemical compound (2k) to carry out substitution reaction, obtain chemical compound (3k).This reaction can with [steps A 2] of preparation method A in carry out under used the same terms.
[step K 2]
In this step, use chemical compound (3k) and chemical compound (4k) to carry out substitution reaction, obtain chemical compound (5k).
Chemical compound (5k) can be for example by making chemical compound (3k) and mixture (4k) at solvent such as methanol, ethanol, 1-Methyl-2-Pyrrolidone, 1, in 4-diox, oxolane or the dimethoxy-ethane, or do not having under the condition of solvent, prepared in reaction obtains under 20 ℃-200 ℃ temperature.Yet reaction condition is not limited thereto.
[step K 3]
In this step, chlorinated compound (5k) obtains chemical compound (6k).This reaction can with [the step D7] of preparation method D in carry out under used the same terms.
[step K 4]
In this step, chemical compound (6k) and chemical compound (7k) reaction obtain chemical compound (8k).This reaction can with [steps A 6] of preparation method A in carry out under used the same terms.
[step K 5]
In this step, remove the R of chemical compound (8k) P5, obtain chemical compound (9k).
R P5Deprotection reaction can remove-carrying out under the standard reaction condition of NH-protecting group.
For example, work as R P5During for benzyl, this reaction can be used the liquefied ammonia of metal such as lithium or sodium, carries out under-78 ℃ to-30 ℃ temperature.
[step K 6]
In this step, use chemical compound (9k) and chemical compound (10k) to carry out substitution reaction, obtain chemical compound (11k).This reaction can with [steps A 4] of preparation method A in carry out under used the same terms.
[step K 7]
In this step, remove the R of chemical compound (11k) P3, obtain chemical compound (12k).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
Preparation method L
[step L1]
In this step, chemical compound (1l) reacts in the presence of oxidant with chemical compound (2l), obtains chemical compound (3l).
Oxidant comprises salt such as iron chloride (III).Solvent comprises methanol, second alcohol and water.This reaction can be carried out under 20 ℃-100 ℃ temperature.
When this reaction causes-R P3When removing, protect again-NH-by protective reaction.Especially, for example work as R P3During for tert-butoxycarbonyl, this reaction can be used reagent such as Bis(tert-butoxycarbonyl)oxide, at solvent such as dichloromethane, chloroform, N, in dinethylformamide or the oxolane, at alkali such as pyridine, 4-aminopyridine, triethylamine or N, the N-diisopropylethylamine exists down, carries out under 0 ℃-80 ℃ temperature.Yet this reaction is not limited thereto.
[step L2]
In this step, chemical compound (3l) and chemical compound (4l) reaction obtain chemical compound (5l).This reaction can with [steps A 4] of preparation method A in carry out under used the same terms.
[step L3]
In this step, remove the R of chemical compound (5l) P3, obtain chemical compound (6l).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
Preparation method M
[step M1]
In this step, chemical compound (1m) and chemical compound (2m) reaction obtain chemical compound (3m).This reaction can with [steps A 6] of preparation method A in carry out under used the same terms.
[step M2]
In this step, chemical compound (3m) and chemical compound (4m) reaction obtain chemical compound (5m).This reaction can with [steps A 4] of preparation method A in carry out under used the same terms.
[step M3]
In this step, remove the R of chemical compound (5m) P3, obtain chemical compound (6m).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
Preparation method N
Figure A0382539400591
[step N1]
In this step, chemical compound (1n) and allyl amine reaction obtain chemical compound (2n).
This reaction can be carried out under 20 ℃-150 ℃ temperature.The solvent that is used for this reaction comprises methanol, ethanol, water and its mixed solvent.
[step N2]
In this step, when chlorinated compound (2n), chemical compound (2n) is reduced, and obtains chemical compound (3n).
Reducing agent comprises pink salt such as stannic chloride.Solvent comprises concentrated hydrochloric acid.This reaction can be carried out under 20 ℃-150 ℃ temperature.
[step N3]
In this step, chemical compound (3n) and N, N '-two succinimidyl carbonate (disuccinimidylcarbonate) reaction obtains chemical compound (4n).
This reaction can use solvent such as acetonitrile or oxolane to finish.This reaction can be carried out under 20 ℃-100 ℃ temperature.
[step N4]
In this step, chemical compound (4n) and chemical compound (5n) reaction obtain chemical compound (6n).This reaction can with [steps A 4] of preparation method A in carry out under used the same terms.
[step N5]
In this step,, obtain chemical compound (7n) by removing pi-allyl in the chemical compound (6n).
Chemical compound (7n) can be for example by making chemical compound (6n) and osmic acid and sodium metaperiodate at solvent such as oxolane, 1,4-diox, 1, in 2-dimethoxy-ethane or the water, prepared in reaction obtains under 20 ℃-100 ℃ temperature.Yet reaction condition is not limited to this example.
[step N6]
In this step, chlorinated compound (7n) obtains chemical compound (8n).
Reaction condition is had no particular limits.This reaction can be carried out under the standard reaction condition of chlorination reaction being used for.Chemical compound (8n) can in solvent such as phosphorus oxychloride, prepare under 0-150 ℃ temperature for example by using reagent such as phosphorus pentachloride.
[step N7]
In this step, chemical compound (8n) and chemical compound (9n) reaction obtain chemical compound (10n).This reaction can with [steps A 6] of preparation method A in carry out under used the same terms.
[step N8]
In this step, remove the R of chemical compound (10n) P3, obtain chemical compound (11n).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
Preparation method O
Figure A0382539400611
[step O1]
In this step, the hydroxyl of oxidized compound (1o) obtains chemical compound (2o).This reaction can with [the step I2] of preparation method I in carry out under used the same terms.
[step O2]
In this step, chemical compound (2o) reacts in the presence of alkali with the diethyl phosphonyl ethyl acetate, obtains chemical compound (3o).
Alkali comprises sodium hydride and diisopropylaminoethyl lithium.Solvent for example comprises, oxolane and N, N-dimethylformamide.This reaction can be carried out under 0 ℃-100 ℃ temperature.
[step O3]
In this step, the ester of hydrolysis compound (3o) obtains chemical compound (4o).This reaction can with [the step C16] of preparation method C in carry out under used the same terms.
[step O4]
In this step, chemical compound (4o) reacts in the presence of alkali with diphenyl phosphoryl azide, obtains chemical compound (5o).
The solvent that is used for this reaction comprises toluene, the tert-butyl alcohol, oxolane and dichloromethane.Alkali comprises tertiary amine such as triethylamine and diisopropylethylamine.This reaction can be carried out under-50 ℃ to 50 ℃ temperature.
[step O5]
In this step, chemical compound (5o) carries out rearrangement reaction, obtains chemical compound (6o).
This reaction can be finished under 50 ℃-100 ℃ temperature in the tert-butyl alcohol.
[step O6]
In this step, the itrile group of hydrolysis compound (6o) obtains chemical compound (7o).This reaction can with [the step H1] of preparation method H in carry out under used the same terms.
[step O7]
In this step, chemical compound (7o) and acid reaction obtain chemical compound (8o).
Acid comprises hydrochloric acid, sulphuric acid and trifluoroacetic acid.Solvent comprises methanol, ethanol, 1,4-diox, water and its mixture.This reaction can be carried out under 0 ℃ to 50 ℃ temperature.
Preparation method P
Figure A0382539400621
[step P1]
In this step, (1p) is protected for chemical compound, obtains chemical compound (2p).
Be generally used for protecting the typical N H group-protection reagent of NH group to can be used as NH group-protection reagent.For example work as R P3During for tert-butoxycarbonyl, this reaction can be under 0 ℃-80 ℃ temperature, use reagent such as Bis(tert-butoxycarbonyl)oxide, at solvent such as dichloromethane, chloroform, N, in dinethylformamide and the oxolane, at alkali such as pyridine, 4-aminopyridine, triethylamine and N, the N-diisopropylethylamine is finished under existing.
[step P2]
In this step, chemical compound (2p) and chemical compound (3p) reaction obtain chemical compound (4p).This reaction can with [steps A 2] of preparation method A in carry out under used the same terms.
[step P3]
In this step, remove the R of chemical compound (4p) P3, obtain chemical compound (5p).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
Preparation method Q
[step Q1]
In this step, hydrolysis compound (1q) obtains chemical compound (2q).
Reaction dissolvent comprises oxolane, methanol and ethanol.Acid comprises mineral acid example hydrochloric acid and sulphuric acid.This reaction can be carried out under 0 ℃-100 ℃ temperature.
[step Q2]
In this step, the hydroxyl of oxidized compound (2q) obtains chemical compound (3q).This reaction can with [the step I2] of preparation method I in carry out under used the same terms.
[step Q3]
In this step, chemical compound (3q) and methylbenzene methoxycarbonyl amino (dimethoxy phosphoryl) acetas, reaction obtains chemical compound (4q) in the presence of alkali.
Alkali comprises sodium hydride, potassium tert-butoxide and 8-diazabicylo [5.4.0]-7-endecatylene.Solvent comprises dichloromethane, oxolane and N, dinethylformamide.This reaction can be carried out under 0 ℃-100 ℃ temperature.
[step Q4]
In this step, chemical compound (4q) and Feldalat NM reaction obtain chemical compound (5q).
Methanol can be used as solvent.This reaction can be carried out under 0 ℃-80 ℃ temperature.
[step Q5]
In this step, chemical compound (5q) and chemical compound (6q) reaction obtain chemical compound (7q).This reaction can with [steps A 2] of preparation method A in carry out under used the same terms.
[step Q6]
In this step, chemical compound (7q) and acid reaction obtain chemical compound (8q).This reaction can with [the step O7] of preparation method O in carry out under used the same terms.
[step Q7]
In this step, remove the R of chemical compound (8q) P3, obtain chemical compound (9q).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
[step Q8]
In this step, chemical compound (7q) and ammonia reaction obtain chemical compound (10q).
Reaction dissolvent comprises methanol, second alcohol and water.This reaction can be carried out under 20 ℃-150 ℃ temperature.
[step Q9]
In this step, remove the R of chemical compound (10q) P3, obtain chemical compound (11q).This reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
Preparation method R
Figure A0382539400661
[step R1]
In this step, chemical compound (1r) obtains chemical compound (3r) with chemical compound (2r) prepared in reaction.This is reflected under the same terms used in [steps A 6] with preparation method A and carries out.
[step R2]
In this step, substituent group is incorporated into the amino group on the 7-position of chemical compound (3r) by the substitution reaction between chemical compound (3r) and the chemical compound (3r-2), and removes R then P3, prepare chemical compound (4r).
With [steps A 4] of preparation method A in carry out this substitution reaction under used the same terms.
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
Preparation method S
[step S1]
In this step, substituent group is incorporated into the amino group on the 7-position of chemical compound (1s) by the substitution reaction between chemical compound (1s) and the chemical compound (1s-2), prepare chemical compound (2s).
With [steps A 4] of preparation method A in carry out this substitution reaction under used the same terms.
[step S2]
In this step, chemical compound (2s) obtains chemical compound (3s) with the halide reagent prepared in reaction.
This halogenation with preparation method A [steps A 5] in carry out under used the same terms.
[step S3]
In this step, chemical compound (3s) and chemical compound (4s) reaction, and remove R then P3Prepare chemical compound (5s).
This coupling reaction with preparation method A [steps A 6] in carry out under used the same terms.
This R P3Deprotection reaction can with [steps A 13] of preparation method A in carry out under used the same terms.
Preparation method T
Figure A0382539400671
[step T1]
In this step, substituent group is incorporated into the amino group on the 7-position of chemical compound (1t) by the substitution reaction between chemical compound (1t) and the chemical compound (1t-2), prepare chemical compound (2t).
With [steps A 4] of preparation method A in carry out this substitution reaction under used the same terms.
[step T2]
In this step, chemical compound (2t) obtains chemical compound (4t) with chemical compound (3t) prepared in reaction.
This is reflected under the same terms used in [steps A 6] with preparation method A and carries out.
[step T3]
In this step,, and remove R then with chemical compound (4t) alkylation on the 1-position P3Prepare chemical compound (5t).
This alkylated reaction with preparation method A [steps A 2] in carry out under used the same terms.
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
[step T4]
In this step, remove the R of chemical compound (4t) P3Prepare chemical compound (6t).
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
Preparation method U
Figure A0382539400681
[step U1]
In this step, substituent group is incorporated into the amino group on the 7-position of chemical compound (1u) by the substitution reaction between chemical compound (1u) and the chemical compound (1u-2), prepare chemical compound (2u).
With [steps A 4] of preparation method A in carry out this substitution reaction under used the same terms.
[step U2]
In this step, chemical compound (2u) obtains chemical compound (3u) with the halide reagent prepared in reaction.
This halogenation with preparation method A [steps A 5] in carry out under used the same terms.
[step U3]
In this step, chemical compound (3u) obtains chemical compound (5u) with chemical compound (4u) prepared in reaction.
This is reflected under the same terms used in [steps A 6] with preparation method A and carries out.
[step U4]
In this step,, and remove R then with chemical compound (5u) alkylation on the 1-position P3Prepare chemical compound (6u).
This alkylated reaction with preparation method A [steps A 2] in carry out under used the same terms.
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
Preparation method V
(wherein each symbol as defined above; And " alkyl " represents C 1-6Alkyl.)
[step V1]
In this step, with chemical compound (1v) alkylation on the 1-position, and hydrolysis prepares chemical compound (2v) then.
Alkylating reaction condition is had no particular limits.For example, this alkylating chemical compound can be by in the presence of alkali such as Lithium hydrate, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, hydrofining, butyl lithium, lithium methide, two (front three is silica-based) Lithamide., two (front three is silica-based) Sodamide. or two (front three is silica-based) potassamide; At solvent such as dimethyl sulfoxide, N, in dinethylformamide, N-Methyl pyrrolidone, diox, oxolane or the toluene; Under 0 ℃-150 ℃ temperature, the chemical compound of heat preserving type (1v-2) representative such as methyl bromoacetate or bromoacetate prepare.
Reaction condition to hydrolysis has no particular limits.For example, this reaction can be used Lithium hydrate, sodium hydroxide or potassium hydroxide aqueous solution; At solvent such as methanol, ethanol, propanol, dimethyl sulfoxide, N, in dinethylformamide, N-Methyl pyrrolidone, diox or the oxolane; Under 0 ℃-150 ℃ temperature, carry out.
[step V2]
In this step, remove the R of chemical compound (2v) P3Prepare chemical compound (3v).
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
[step V3]
In this step, chemical compound (2v) amidatioon is prepared chemical compound (4v).
Amidated reaction condition is had no particular limits.For example, this reaction can be used acylating reagent such as ethyl chloroformate or chloro-carbonic acid isobutyl; At organic base such as triethylamine or N, the N-diisopropylethylamine exists down; At solvent such as acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, 1 are in 4-diox, oxolane or the dimethoxy-ethane; Carry out under 0 ℃-150 ℃ temperature with corresponding amine.
[step V4]
In this step, remove the R of chemical compound (4v) P3Prepare chemical compound (5v).
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
[step V5]
In this step, alkylated compound (5v), and remove R then P3Prepare chemical compound (6v).
This alkylated reaction with preparation method A [steps A 2] in carry out under used the same terms.
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
[step V6]
In this step, amidatioon chemical compound (2v), and remove R then P3Prepare chemical compound (6v).
Amidated reaction condition is had no particular limits.For example, this amidation process can use condensation reagent as 1,1 '-carbonyl dimidazoles or diethyl phosphorocyanidate; In solvent such as organic base such as triethylamine, carry out.This reaction can be carried out to the temperature range of room temperature in ice-cold approximately temperature.
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
Preparation method W
Figure A0382539400711
[step W1]
In this step, with chemical compound (1w) hydroxyl-imidization, and the hydroxyl that generates handled by sulfonylation, remove R subsequently P3Prepare chemical compound (2w).
Reaction condition to hydroxyl imideization has no particular limits.For example, this hydroxyl imide reaction can be used reagent example hydrochloric acid azanol; In the presence of alkali such as potassium acetate or sodium acetate; At solvent such as water, methanol, ethanol, propanol, dimethyl sulfoxide, N, carry out in dinethylformamide, N-Methyl pyrrolidone, diox, oxolane or the toluene.
Reaction condition to sulfonylation has no particular limits.For example, this sulfonylation can use mesyl chloride, toluene sulfochloride, 4-nitrobenzene sulfonyl chloride etc.; At alkali such as triethylamine, diisopropylethylamine, pyridine or N, the N-dimethyl aminopyridine exists down; In solvent such as dichloromethane, chloroform, diox, oxolane, toluene or pyridine; Under 0 ℃-150 ℃ temperature, carry out.
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
[step W2]
In this step, remove the R of chemical compound (1w) P3Prepare chemical compound (3w).
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
Preparation method X
[step X1]
In this step, reducing compound (1x) prepares chemical compound (2x).
Reaction condition is had no particular limits.For example, this reaction can be used and go back original reagent such as lithium borohydride, sodium borohydride or potassium borohydride; At solvent such as methanol, ethanol, acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, 1 are in the mixed solution of 4-diox, oxolane, dimethoxy-ethane or these solvents; Under 0 ℃-150 ℃ temperature, carry out.
[step X3]
In this step, alkylated compound (2x) prepares chemical compound (4x).
Alkylating reaction condition is had no particular limits.For example this alkylated reaction can use haloalkyl; In the presence of alkali such as lithium hydride, sodium hydride, hydrofining, Lithium hydrate, sodium hydroxide or potassium hydroxide; At solvent such as methanol, ethanol, acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, 1 carry out in 4-diox, oxolane or the dimethoxy-ethane.
[step X5]
In this step, fluorinated compound (2x) prepares chemical compound (6x).
Reaction condition is had no particular limits.For example, this reaction can use fluorization agent as three (dimethylamino sulfuric ester) trifluoride (Tris dimethylaminosulfate trifluoride); At solvent such as dichloromethane, 1,2-dichloroethanes, acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, 1 are in 4-diox, oxolane or the dimethoxy-ethane; Under-78 ℃-150 ℃ temperature, carry out.
[step X7]
In this step, fluorinated compound (1x) prepares chemical compound (8x).
Reaction condition is had no particular limits.For example, this reaction can use fluorization agent as three (dimethylamino sulfuric ester) trifluoride; At solvent such as dichloromethane, 1,2-dichloroethanes, acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, 1 are in 4-diox, oxolane or the dimethoxy-ethane; Under-78 ℃-150 ℃ temperature, carry out.
[step X9]
In this step, chemical compound (2x) is carried out the Wittig-Horner-Emmons reaction, prepare chemical compound (10x).
Reaction condition is had no particular limits.For example, this reaction can be used reagent such as microcosmic salt or phosphate ester; In the presence of alkali such as lithium hydride, sodium hydride, hydrofining, potassium tert-butoxide or butyl lithium; At solvent such as dichloromethane, 1,2-dichloroethanes, acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, 1 are in 4-diox, oxolane or the dimethoxy-ethane; Under-78 ℃-150 ℃, carry out.
[step X11]
In this step, reducing compound (10x) prepares chemical compound (12x).
Reductive reaction condition is had no particular limits.For example, this reduction can be in the presence of metallic catalyst such as palladium carbon, platinum oxide or Raney Ni; At solvent such as methanol, ethanol, propanol, dimethyl sulfoxine, N, in dinethylformamide, N-Methyl pyrrolidone, diox, oxolane or the toluene; Under nitrogen atmosphere, under 0 ℃-150 ℃ temperature, carry out.
[step X2], [step X4], [step X6], [step X8], [step X10] and [step X12]
Remove R by chemical compound (2x), (4x), (6x), (8x), (10x) with (12x) respectively P3, prepare chemical compound (3x), (5x), (7x), (9x), (11x) and (13x).
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
Preparation method Y
Figure A0382539400741
[step Y1]
In this step, hydrolysis compound (1y) prepares chemical compound (2y).
Reaction condition to hydrolysis has no particular limits.For example, this hydrolysis can be used the aqueous solution as Lithium hydrate, sodium hydroxide, potassium hydroxide; At solvent such as methanol, ethanol, acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, 1 are in 4-diox, oxolane or the dimethoxy-ethane; Under 0 ℃-150 ℃ temperature, carry out.
[step Y3]
In this step, amidatioon chemical compound (2y) prepares chemical compound (4y).
This amidation process with preparation method V [step V6] in carry out under used the same terms.
[step Y2] and [step Y4]
In this step, remove R by chemical compound (2y) with (4y) respectively P3, prepare chemical compound (3y) and (5y).
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
Preparation method Z
The method is a kind of replacement method that generates the chemical compound described in the preparation method U (2u).
Figure A0382539400751
[step Z1]
In this step, the amino group on protection chemical compound (1z) the 7-position prepares chemical compound (2z).
Kind, reaction condition and other variable to the group that is used to protect amino group have no particular limits.For example, when blocking group was benzyl, this reaction can be used alkylating reagent such as benzyl bromide a-bromotoluene; In the presence of alkali such as cesium carbonate, lithium carbonate, sodium carbonate or potassium carbonate; At solvent such as acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, 1 are in 4-diox, oxolane or the dimethoxy-ethane; Under 0 ℃-150 ℃ temperature, carry out.
[step Z2]
In this step, the 1-position of protection chemical compound (2z) prepares chemical compound (3z).
Kind, reaction condition and other variable to the group that is used to protect amino group have no particular limits.For example, when blocking group was oxy acid methyl neopentyl, this reaction can be used alkylating reagent such as chloromethyl pivalate; In the presence of alkali such as cesium carbonate, lithium carbonate, sodium carbonate or potassium carbonate; At solvent such as acetonitrile, N, dinethylformamide, N-Methyl pyrrolidone, 1 are in 4-diox, oxolane or the dimethoxy-ethane; Under 0 ℃-150 ℃ temperature, carry out.
[step Z3]
In this step, the amino group on protection chemical compound (3z) the 7-position prepares chemical compound (4z).
This reaction condition can change according to the kind of used blocking group.For example, when protecting group was benzyl, this reaction can be in the presence of metallic catalyst such as palladium carbon, platinum oxide or Raney Ni; At solvent such as methanol, ethanol, propanol, dimethyl sulfoxide, N, in dinethylformamide, N-Methyl pyrrolidone, diox, oxolane or the toluene; Under nitrogen atmosphere, under 0 ℃-150 ℃, carry out.
[step Z4]
In this step, substituent group is incorporated into the amino group on the 7-position of chemical compound (4z) by the substitution reaction between chemical compound (4z) and the chemical compound (4z-2), prepare chemical compound (5z).
With [steps A 4] of preparation method A in carry out this substitution reaction under used the same terms.
[step Z5]
In this step, by the protecting group of removing in the chemical compound (5z) on the 1-position, prepare chemical compound (6z) (=2u).
This reaction condition can change according to the kind of used blocking group.For example, when protecting group was oxy acid methyl neopentyl, this reaction can be used alkali such as sodium methoxide, sodium hydride or diazabicylo 11 carbon-7-alkene; The mixed solvent of solvent such as methanol or methanol and oxolane; Under 0 ℃-150 ℃ temperature, carry out.
Preparation method AA
Figure A0382539400761
[steps A A1]
In this step, chemical compound (1aa) and halide reagent reaction prepare chemical compound (2aa).
This halogenation with preparation method A [steps A 5] in carry out under used the same terms.
[steps A A2]
In this step, chemical compound (2aa) and chemical compound (3aa) reaction prepare chemical compound (4aa).
This is reflected under the same terms used in [steps A 6] with preparation method A and carries out.
[steps A A3]
In this step, remove the protecting group on the 7-bit amino group in the chemical compound (4aa), prepare chemical compound (5aa).
This deprotection reaction with preparation method Z [step Z3] in carry out under used the same terms.
[steps A A4]
In this step, substituent group is incorporated into the amino group on the 7-position of chemical compound (5aa) by the substitution reaction between chemical compound (5aa) and the chemical compound (5aa-2), prepare chemical compound (6aa).
With [steps A 4] of preparation method A in carry out this substitution reaction under used the same terms.
[steps A A5]
In this step, remove the protecting group on the 1-position in the chemical compound (6aa), prepare chemical compound (7aa).
This deprotection reaction with preparation method Z [step Z5] in carry out under used the same terms.
[steps A A6]
In this step, remove the R of chemical compound (7aa) P3Prepare chemical compound (8aa).
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
Preparation method BB
Figure A0382539400781
[step BB1]
In this step, the 1-and the 3-position of protection chemical compound (1bb) prepare chemical compound (2bb).
This reaction with preparation method Z [step Z2] in carry out under used the same terms.
[step BB2]
In this step, remove the protecting group on the 7-bit amino group in the chemical compound (2bb), prepare chemical compound (3bb).
This deprotection reaction with preparation method Z [step Z3] in carry out under used the same terms.
[step BB3]
In this step, substituent group is incorporated into the amino group on the 7-position of chemical compound (3bb) by the substitution reaction between chemical compound (3bb) and the chemical compound (3bb-2), prepare chemical compound (4bb).
With [steps A 4] of preparation method A in carry out this substitution reaction under used the same terms.
[step BB4]
In this step, chemical compound (4bb) and halide reagent reaction prepare chemical compound (5bb).
This halogenation with preparation method A [steps A 5] in carry out under used the same terms.
[step BB5]
In this step, chemical compound (5bb) and chemical compound (6bb) reaction prepare chemical compound (7bb).
This is reflected under the same terms used in [steps A 6] with preparation method A and carries out.
[step BB6]
In this step, remove the protecting group on the 3-position in the chemical compound (7bb), prepare chemical compound (8bb).
This deprotection reaction with preparation method Z [step Z5] in carry out under used the same terms.
[step BB7]
In this step, by the substitution reaction between chemical compound (8bb) and the chemical compound (8bb-2) substituent group is incorporated on the 3-position of chemical compound (8bb), prepare chemical compound (9bb).
With [steps A 4] of preparation method A in carry out this substitution reaction under used the same terms.
[step BB8]
In this step, remove the protecting group on the 1-position in the chemical compound (9bb), prepare chemical compound (10bb).
This deprotection reaction with preparation method Z [step Z5] in carry out under used the same terms.
[step BB9]
In this step, remove the R of chemical compound (10bb) P3, prepare chemical compound (11bb).
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
[step BB10]
In this step, by the substitution reaction between chemical compound (10bb) and the chemical compound (10bb-2) substituent group is incorporated on the 3-position of chemical compound (10bb), remove R then P3Prepare chemical compound (12bb).
With [steps A 4] of preparation method A in carry out this substitution reaction under used the same terms.
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
Preparation method CC
Figure A0382539400801
[step CC1]
In this step, by the substitution reaction between chemical compound (1cc) and the chemical compound (1cc-2) substituent group is incorporated on the 3-position of chemical compound (1cc), prepare chemical compound (2cc).
With [steps A 4] of preparation method A in carry out this substitution reaction under used the same terms.
[step CC2] [step CC3]
In these steps, remove chemical compound (1cc) and R (2cc) respectively P3, prepare chemical compound (3cc) and (4cc).
R P3Deprotection reaction with preparation method A [steps A 13] in carry out under used the same terms.
Aforesaid method is preparation The compounds of this invention (I) and representational method (II).Used initial compounds and all ingredients can be the form of salt or hydrate or solvate according to used starting material, solvent types etc. in preparing the method for The compounds of this invention, and then it are not limited as long as they can not suppress this reaction.The kind of solvent for use is decided with the kind of used initial compounds, reagent etc., if they can not suppress this reaction and in a way the solubilized starting material then to its not restriction.When The compounds of this invention (I) and (II) obtaining with free form, according to conventional methods, this chemical compound can be converted into salt or hydrate, and it is above-claimed cpd (I) and possible form (II).
During when The compounds of this invention (I) with (II) with salt or hydrate acquisition, this product can be converted into above-claimed cpd (I) and free form (II) according to the method for routine.
In addition, the various isomers of The compounds of this invention (I) and (II) (for example geometric isomer, enantiomer, rotamer, stereoisomer and tautomer based on asymmetric carbon atom) can comprise the method for recrystallization, diastereoisomeric salt by typical separation method, based on separating of enzyme and various chromatographic processes (for example thin layer chromatography, column chromatography and gas chromatography) carrying out purification and separate.
Pharmaceutical preparation of the present invention can be that the preparation of pharmaceutical formulations that DPPIV inhibitor and biguanide reagent maybe can improve active form GLP-2 effect in the blood obtains by the mixed active composition.Can be separately or in conjunction with the above-mentioned active component of configuration, and they can mix with pharmaceutically suitable carrier, excipient, binding agent etc.The dosage form of said medicine preparation comprises oral formulations, for example granule, microgranule, powder, tablet, coated tablet, capsule and syrup; And non-oral formulation, injection (intravenous injection, subcutaneous injection agent, intramuscular injection agent etc.) for example, suppository and external preparation (transdermal therapeutic agent, ointment etc.).
This preparation can be by using typical excipient, binding agent, disintegrating agent, lubricant, coloring agent, aromatic; And if need, stabilizing agent, emulsifying agent, absorption enhancer, detergent, pH regulator agent, antiseptic, antioxidant etc., and the common material that is used as pharmaceutical preparation composition according to conventional methods prepares.These materials for example comprise that (1) animal and plant oil is as Oleum Glycines, Adeps Bovis seu Bubali and synthetic glyceride; (2) hydrocarbon such as liquid Paraffin, squalane and hard paraffin; (3) oils and fats such as octyl group dodecyl myristate (octyldodecyl myristate) and isopropyl myristate; (4) the pure and mild behenyl alcohol of higher alcohol such as cetearyl alcohol; (5) silicones; (6) silicone oil; (7) detergent such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, fatty acid glyceride, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated Oleum Ricini and ethylene oxide-oxypropylene block copolymer; (8) water-soluble polymer such as hydroxyethyl-cellulose, polyacrylic acid, CVP Carbopol ETD2050, Polyethylene Glycol, polyvinylpyrrolidone and methylcellulose; (9) lower alcohol such as ethanol and isopropyl alcohol; (10) polyhydric alcohol such as glycerol, propylene glycol, dipropylene glycol and sorbitol; (11) sugar is as dextrose plus saccharose; (12) inorganic powder such as anhydrous silicic acid, aluminium-magnesium silicate and aluminium silicate; (13) pure water.
Excipient comprises for example lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystal fibre element and silicon dioxide.Binding agent comprises for example polyvinyl alcohol, polyvinylether, methylcellulose, ethyl cellulose, arabic gum, gum tragacanth, gelatin, lac, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, propylene glycol-ethylene oxide block copolymer, meglumine, calcium citrate, dextrin and pectin.Disintegrating agent comprises for example starch, agar, gelatin powder, microcrystalline Cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin and carboxymethylcellulose calcium.Lubricant comprises for example magnesium stearate, Talcum, Polyethylene Glycol, silicon dioxide and hydrogenated vegetable oil.Coloring agent comprises those pharmaceutically acceptable coloring agent.Aromatic comprises cocoa powder, Mentholum, aromatic powder, Oleum menthae, Borneolum Syntheticum and Cortex Cinnamomi powder.Antioxidant comprises those pharmaceutically acceptable antioxidants, as ascorbic acid and alpha-tocopherol.
This oral formulations can prepare by following method: with active component and excipient; And if need mixing such as binding agent, disintegrating agent, lubricant, coloring agent, aromatic; And mixture is mixed with powder, microgranule, granule, tablet, coated tablet, capsule etc. according to the method for routine.Tablet and granule can apply with sugar or gelatin, or can apply other suitable coating if need.Can be by with chemical compound of the present invention and pH regulator agent, solubilizing agent, isotonic agent etc., and, be disposed for solution such as the syrup or the injection of administration according to the method for routine as if mixing with secondary solubilizer, stabilizing agent, buffer, suspending agent etc.But this solution of lyophilizing.The example of preferred suspending agent is: methylcellulose, polysorbate80, hydroxyethyl-cellulose, arabic gum, gum tragacanth, sodium carboxymethyl cellulose and polyoxyethylene 20 sorbitan monolaurate.The example of preferred secondary solubilizer is: polyoxyethylene hydrogenated Oleum Ricini, polysorbate80, nicotiamide and polyoxyethylene 20 sorbitan monolaurate.The example of preferred stabilizing agent is: sodium sulfite, sodium metasulfite (sodium metasulfite), and ether.The example of preferred antiseptic is: to the oxybenzoic acid methyl ester, to oxybenzoic acid ethyl ester, sorbic acid, phenol, cresol and chlorocresol.For the method kind for preparing external preparation without limits, and said preparation can be prepared by a conventional method to obtain.Can comprise for substrate being used to prepare medicine, quasi drugs, enamel and other material various commonly used, comprise animal and plant oil, mineral oil, synthetic ester lubricant, wax, higher alcohol, fatty acid, silicone oil, detergent, phospholipid, alcohol, polyhydric alcohol, water-soluble polymer, clay mineral and pure water.In addition, if need external preparation of the present invention can contain pH regulator agent, antioxidant, chelating agen, antibacterial/antifungal, coloring agent and aromatic.In addition, if need external preparation of the present invention also can contain to induce the medicament of differentiation, promotion blood flow, activating cell, with antibacterial, antibiotic medicine, vitamin, aminoacid, wetting agent, keratolytic and other.
According to the present invention, the kind of pharmaceutical preparation medication is had no particular limits.DPPIV inhibitor and biguanide reagent maybe can strengthen the pharmaceutical preparation of active form GLP-2 effect in the blood can be used when administration simultaneously.For example, medication can comprise that (1) gives the preparation that pharmaceutical preparation that DPPIV inhibitor and biguanide reagent maybe can strengthen active form GLP-2 effect in the blood combines and is configured to; (2) two kinds of preparations are given simultaneously, it can obtain by disposing the pharmaceutical preparation that DPPIV inhibitor and biguanide reagent maybe can strengthen active form GLP-2 effect in the blood respectively; (3) (for example give two kinds of preparations respectively at different time, according to the DPPIV inhibitor and then biguanide reagent maybe can strengthen the order of the pharmaceutical preparation of the effect of active form GLP-2 in the blood or opposite order with they administrations), it can obtain by disposing the pharmaceutical preparation that DPPIV inhibitor and biguanide reagent maybe can strengthen active form GLP-2 effect in the blood respectively.
Dosage according to pharmaceutical preparation of the present invention can be selected based on the standard dose of every kind of medicine.This dosage can suitably be selected based on the kind of seriousness, dosage form and the disease of patient's age, body weight, sex, symptom.The DPPIV inhibitor that gives when per os or parenteral for (S)-1-((3-hydroxyl-1-adamantyl) amino) acetyl group-2-Cyanopyrolidine or (S)-during l-(2-((5-cyanopyridine-2-yl) amino) ethyl-glycyl)-2-Cyanopyrolidine; this dosage can typically be selected from 0.1-250mg/ adult/sky, preferred 1-100mg/ adult/sky.When the DPPIV inhibitor that gives when per os or parenteral was isoleucine Thiazolidine, isoleucine pyrrolidine or valine pyrrolidine, this dosage can typically be selected from 0.01-2.0mg/kg/ days, preferred 0.01-1.0mg/kg/ days.When the DPPIV inhibitor is formula (I) or (II) chemical compound or its salt or the hydrate of representative, and when giving the adult with its per os, this dosage can typically be selected from 0.03-1000mg/ days, and preferred 0.1-500mg/ days, more preferably 0.1-100mg/ days.When the DPPIV inhibitor is formula (I) or (II) chemical compound or its salt or the hydrate of representative, and when giving the adult with it with parenteral, this dosage can typically be selected from about 1-3000 μ g/kg/ days, preferably about 3-1000 μ g/kg/ days.When DPPIV inhibitor and other reagent when for example biguanide reagent uses simultaneously, this dosage can typically be selected from 10-2500mg/ adult/sky, and is preferably 100-1000mg/ adult/sky.
In the present invention, DPPIV inhibitor and biguanide reagent all can be taken once or the aforesaid daily dose of several.
According to the dosage of each reagent in the pharmaceutical preparation of the present invention than can suitably selecting based on the kind of seriousness, dosage form and the disease of patient's age, body weight, sex, symptom.For example, the body weight between DPPIV inhibitor and the biguanide reagent: the dosage weight ratio can typically fall into 1: 1-1: 2500, preferred 1: 10-1: in 250 the scope.
The dosage of (the S)-1-of indication in the literary composition ((3-hydroxyl-1-adamantyl) amino) acetyl group-can be selected from 3-1000 μ g/kg gives.When DPPIV inhibitor and other reagent when for example biguanide reagent uses simultaneously, this dosage can typically be selected from 10-2500mg/ adult/sky, and preferred 100-1000mg/ adult/sky.
As mentioned above formula (I) and (II) chemical compound of the present invention of representative can prepare by the method described in the following embodiment.Yet, chemical compound of the present invention should be defined as specific embodiment as described below in no instance.
[preparation embodiment]
Preparation embodiment 1
4-[1-(2-butyne base)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl] piperazine-1-carboxylic acid tertiary butyl ester
(a) 5-methyl-4-oxo-4,5-glyoxalidine be [4,5-d] pyridazine-1-carboxylic acid tertiary butyl ester also
The 5-methyl-3 that will contain 1.0g, 5-the glyoxalidine also mixture of the oxolane of the Bis(tert-butoxycarbonyl)oxide of 4-dimethylaminopyridine, the 1.6g of [4,5-d] pyridazine-4-ketone, 16mg and 5ml at room temperature stir and spend the night.Then, the tetrahydrofuran solution of 0.5-ml that will contain the Bis(tert-butoxycarbonyl)oxide of 300mg joins in this solution, and with the mixture that generates in the chamber
Relaxing the bowels with purgatives of warm nature stirred 3 hours.The t-butyl methyl ether of 5ml is joined in the reactant mixture, and with mixture with ice-cooled.Filter and collect the crystal that obtains, obtain the title compound of 1.63g.
1H-NMR(CDCl 3)δ1.72(s，9H)3.93(s，3H)8.38(s，1H)8.54(s，1H)
(b) 2-chloro-5-methyl isophthalic acid, 5-glyoxalidine be [4,5-d] pyridazine-4-ketone also
Under nitrogen at 0 ℃ through one hour, the hmds lithium (lithiumhexamethyldisilazide) (1.0M tetrahydrofuran solution) of 8.4ml is added drop-wise to the 5-methyl-4-oxo-4 that contains 1.68g of 300-ml, the 5-glyoxalidine is also in the tetrahydrofuran solution of the hexachlorethane of [4,5-d] pyridazine-1-carboxylic acid tertiary butyl ester and 4.15g.The mixture that generates was stirred 30 minutes.2N ammonia is joined in the solution, and mixture was stirred 3 hours.Then, reaction solution is concentrated into 50ml, and washes with the t-butyl methyl ether of 20ml.With solution concentrated hydrochloric acid acidify.Filter and collect the precipitation that generates, and wash with the t-butyl methyl ether of 10ml water and 10ml successively.Thereby, obtain the title compound of 1.03g.
1H-NMR(DMSO-d6)δ1.45(s，9H)3.72(s，3H)8.33(s，1H)
(c) 3-(2-butyne base)-2-chloro-5-methyl-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone also
Under nitrogen, with the 2-chloro-5-methyl isophthalic acid of 7.72g, 5-glyoxalidine also [4,5-d]-pyridazine-4-ketone is suspended in the oxolane of 400ml, and the triphenylphosphine of 14.22g and the 2-butyne of 3.85g-1-alcohol are added wherein.The mixture that generates is cooled to 0 ℃.Drip the tetrahydrofuran solution that contains 12.55g azoformic acid di-t-butyl ester of 100-ml, and reactant mixture was stirred 3 hours.The concentrating under reduced pressure reactant mixture.The dichloromethane of 50ml and the trifluoroacetic acid of 50ml are joined in the residue, and mixture was stirred 15 hours.The concentrating under reduced pressure reactant mixture.The residue that generates is dissolved in the 400ml ethyl acetate, and with the 5N aqueous sodium hydroxide washes of 200ml.With water layer 100ml ethyl acetate extraction.Organic layer is merged together, through dried over mgso, and concentrating under reduced pressure.With the residue that generates through the silica gel column chromatography purification.Thus, from the part of hexane-ethyl acetate (4: 1) eluting, obtain the 8.78g title compound.
1H-NMR(CDCl 3)δ1.82(t，J＝2.3Hz，3H)3.87(s，3H)5.32(q，J＝2.3Hz，2H)8.19(s，1H)
(d) 4-[1-(2-butyne base)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl] Piperazine-1-carboxylic acid tertiary butyl ester
Under nitrogen, the 1-Methyl-2-Pyrrolidone of 5ml is joined 3-(2-butyne the base)-2-chloro-5-methyl-3 that contains 1.183g, the 5-glyoxalidine is also in the mixture of [4,5-d] pyridazine-4-ketone, 0.829g potassium carbonate and 1.395g piperazine-1-carboxylic acid tertiary butyl ester.The mixture that generates was heated 6 hours in 130 ℃.Reaction mixture, and to wherein adding 50ml water.Then mixture is used the 100ml ethyl acetate extraction.Organic layer is also washed twice with the saturated sodium-chloride water solution of 50ml then with 50ml water.Organic layer is through dried over mgso, and concentrating under reduced pressure.With the residue that generates through the silica gel column chromatography purification.Thereby, from the part of hexane-ethyl acetate (1: 4) eluting, obtain the title compound of 1.916g.
1H-NMR(CDCl 3)δ1.52(s，9H)1.83(t，J＝2.3Hz，3H)3.38-3.42(m，4H)3.61-3.64(m，4H)3.85(s，3H)5.09(q，J＝2.3Hz，2H)8.13(s，1H)
Preparation embodiment 2
4-[7-(2-butyne base)-2,6-two chloro-7H-purine-8-yls] piperazine-1-carboxylic acid tertiary butyl ester (a) 7-(2-butyne base)-3-methyl-3,7-dihydro purine-2,6-diketone
The 1-bromo-2-butyne of 55.3ml and the Anhydrous potassium carbonate of 84.9g are joined the 3-methylxanthine [CAS No.1076-22-8] of 100g and the N of 1000ml, in the mixture of dinethylformamide.The mixture that generates was at room temperature stirred 18 hours.1000ml water is joined in the reaction solution, and mixture was at room temperature stirred 1 hour.The white precipitate that generates is filtered collection.Water also whitens the color solid with t-butyl methyl ether then.Thereby obtain the title compound of 112g.
1H-NMR(DMSO-d6)δ1.82(t，J＝2.2Hz，3H)3.34(s，3H)5.06(q，J＝2.2Hz，2H)8.12(s，1H)11.16(br.s，1H)
(b) 7-(2-butyne base)-8-chloro-3-methyl-3,7-dihydro purine-2,6-diketone
With 7-(2-butyne base)-3-methyl-3 of 112g, 7-dihydro purine-2, the 6-diketone is dissolved in the N of 2200ml, in the dinethylformamide, and the N-chloro-succinimide of 75.3g is added wherein.The mixture that generates was at room temperature stirred 5 hours.2200ml water is joined in the reaction solution, and mixture was at room temperature stirred 1.5 hours.Filter to collect white precipitate, and water and whiten the color solid with t-butyl methyl ether.Therefore obtain the title compound of 117g.
1H-NMR(DMSO-d6)δ1.78(t，J＝2.0Hz，3H)3.30(s，3H)5.06(q，J＝2.0Hz，2H)11.34(br.s，1H)
(c) 7-(2-butyne base)-2,6,8-three chloro-7H-purine
With 7-(2-butyne base)-8-chloro-3-methyl-3 of 2.52g, 7-dihydro purine-2, the mixture of the phosphorus oxychloride of 6-diketone and 100ml stirred 14 hours down in 120 ℃.After reactant mixture cooling, the phosphorus pentachloride of 4.15g is joined in the solution.The mixture that generates was stirred 24 hours in 120 ℃.After reaction solution is cooled to room temperature, solvent evaporated under reduced pressure.Residue is dissolved in the oxolane.This solution is poured in the saturated sodium bicarbonate aqueous solution, and with the mixture ethyl acetate extraction.With organic layer water, the saturated salt washing then that generates, and concentrating under reduced pressure then.(ethyl acetate: purification hexane=1: 3) obtains the title compound of 2.40g to residue through silica gel column chromatography.
1H-NMR(CDCl 3)δ1.82(t，J＝2.4Hz，3H)5.21(q，J＝2.4Hz，2H)
(d) 4-[7-(2-butyne base)-2,6-two chloro-7H-purine-8-yls] piperazine-1-carboxylic acid tertiary butyl ester
With the 7-(2-butyne base)-2,6 of 2.4g, the mixture of 8-three chloro-7H-purine, 1.46g sodium bicarbonate, 2.43g piperazine-1-carboxylic acid tertiary butyl ester and 45ml acetonitrile at room temperature stirred 2 hours 20 minutes.Add 0.73g sodium bicarbonate and 1.21g piperazine-1-carboxylic acid tertiary butyl ester then, and the mixture that generates was at room temperature stirred 1 hour.Reactant mixture is with the extraction of ethyl acetate-water, and with organic layer with the pickling of 1N salt, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure then.Residue grinds with ether.Filter and collect crystallization, and wash with ether.Thereby obtain the title compound of 3.0g white solid.
1H-NMR(DMSO-d6)δ1.42(s，9H)1.83(t，J＝2Hz，3H)3.48-3.55(m，4H)3.57-3.63(m，4H)4.89(q，J＝2Hz，2H)
[embodiment]
Embodiment 1
[7-(2-chlorphenyl)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base oxygen base] Ethyl acetate trifluoro-acetate (trifluoroacetate)
(a) [7-benzyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2,2-dimethyl propylene acid esters
The 7-benzyl xanthine of 8.66g is dissolved in the N of 300ml, in the dinethylformamide, and 1.57g sodium hydride and 7.7ml chloromethyl pivalate is added wherein.With the mixture that generates in stirred overnight at room temperature.Reaction solution is diluted with ethyl acetate, and water and the pickling of 1N salt.Organic layer through anhydrous magnesium sulfate drying, is filtered then.Solvent evaporated under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby obtain the title compound of 2.66g in the part by hexane-ethyl acetate (1: 1) eluting.
1H-NMR(CDCl 3)δ1.18(s，9H)5.45(s，2H)6.06(s，2H)7.34-7.39(m，5H)7.58(s，1H)8.18(s，1H)。
(b) [7-benzyl-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2, the 2-dimethyl propylene Acid esters
With [7-benzyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2 of 2.66g, 2-dimethyl propylene acid esters is dissolved in the N of 30ml, in the dinethylformamide, and 1.6g potassium carbonate and 1ml iodomethane is added wherein.Mixture at room temperature stirred spend the night.Reactant mixture is diluted with ethyl acetate, and water and the pickling of 1N salt.Organic layer through anhydrous magnesium sulfate drying, is filtered then.Solvent evaporated under reduced pressure.Residue is ground with toluene.Obtain the title compound of 2.16g thus.
1H-NMR(CDCl 3)δ1.18(s，9H)3.41(s，3H)5.49(s，2H)6.11(s，2H)7.26-7.39(m，5H)7.57(s，1H)。
(c) [1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2,2-dimethyl propylene acid esters
With [7-benzyl-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2 of 2.349g, 2-dimethyl propylene acid esters is dissolved in the 100ml acetic acid, and the 10% palladium carbon of 1g is added wherein.Mixture at room temperature stirs under hydrogen and spends the night.Filter reaction mixture also concentrates, and obtains the title compound of 1.871g.
1H-NMR(CDCl 3)δ1.19(s，9H)3.48(s，3H)6.17(s，2H)7.83(s，1H)。
(d) [7-(2-chlorphenyl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2, the 2-diformazan The base propionic ester
[1-methyl-2,6-dioxo-1,2 with 1.60g, 6,7-tetrahydrochysene purine-3-yl] methyl 2, the 2-chlorophenylboronic acid of 2-dimethyl propylene acid esters, 1.83g and 1.5g Schweinfurt green (II) are suspended in the N of 30ml, in the dinethylformamide, and with the adding of 3ml pyridine wherein.Mixture was at room temperature stirred 3 days.Reactant mixture is filtered by the short column of filling with silica gel, and filtrate is diluted with ethyl acetate.Organic layer is washed with 1N hydrochloric acid, water and saturated salt, and through anhydrous magnesium sulfate drying, filters then.Concentrated filtrate.Residue is suspended in the ether, and filtering suspension liquid.Filtrate is through the silica gel column chromatography purification.Thereby from the part of hexane-ethyl acetate (3: 2) eluting, obtain the title compound of 724mg.
(e) 4-[7-(2-chlorphenyl)-3-(2,2-dimethyl propylene acyloxy methyl)-1-methyl-2, the 6-dioxo -2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester
With [7-(2-chlorphenyl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2 of 724mg, 2-dimethyl propylene acid esters is suspended in the N of 15ml, in the dinethylformamide, and the N-chloro-succinimide of 760mg is added wherein.Reaction solution stirs and spends the night, and dilutes with ethyl acetate then.With solution with water and the pickling of 1N salt, and, filter then through anhydrous magnesium sulfate drying.Concentrated filtrate.Obtain [8-chloro-7-(2-chlorphenyl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2 of 764mg thus, 2-dimethyl propylene acid esters.This chemical compound mixes with piperazine-1-carboxylic acid tertiary butyl ester of 4g.Mixture in 150 ℃ of heating, and was stirred 3 hours.Ethyl acetate and water are joined in the reactant mixture, and separating mixture.Organic layer 1N salt pickling, and through anhydrous magnesium sulfate drying, filter then.Concentrated filtrate.Residue is through the silica gel column chromatography purification.Thereby from the part of hexane-ethyl acetate (3: 2) eluting, obtain the title compound of 724mg.
(f) 4-[7-(2-chlorphenyl)-1-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1- The carboxylic acid tertiary butyl ester
With 4-[7-(2-chlorphenyl)-3-(2,2-dimethyl propylene acyloxy methyl)-1-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the mixture of 10ml methanol and 20ml oxolane, and the 200mg sodium hydride added wherein.With the mixture that generates in stirred overnight at room temperature.1N hydrochloric acid is joined in the reaction solution, and use the ethyl acetate extraction mixture.Organic layer through anhydrous magnesium sulfate drying, is filtered then.Concentrated filtrate.Residue is suspended in the ether, and filtering mixt.Thereby obtain the title compound of 450mg.
1H-NMR(DMSO-d 6)δ1.35(s，9H)3.04(s，3H)3.06-3.12(m，4H)3.17-3.22(m，4H)7.48(dt，J＝1.6，7.6Hz，1H)7.53(dt，J＝2.0，7.6Hz，1H)7.63(dd，J＝2.0，8.0Hz，1H)7.65(dd，J＝1.6，8.0Hz，1H)。
(g) 4-[2-chloro-7-(2-chlorphenyl)-1-methyl-6-oxo-6,7-two-hydrogen-1H-purine-8-yl] piperazine-1- Carboxylic acid tertiary butyl ester (g-1), and 4-[2,6-two chloro-7-(2-chlorphenyl)-7H-purine-8-yl] piperazine-1-carboxylic acid uncle Butyl ester (g-2)
With 4-[7-(2-chlorphenyl)-1-methyl-2 of 78mg, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 3ml phosphorus oxychloride, and mixture spent the night 120 ℃ of stirrings.Concentrated reaction solution, and residue is dissolved in the 1ml oxolane.This solution is poured in the suspension that contains the 100mg sodium bicarbonate aqueous solution that comprises 50mg Bis(tert-butoxycarbonyl)oxide, 1ml oxolane and 0.5ml.The mixture that generates was at room temperature stirred 3 hours.Reactant mixture is diluted with ethyl acetate, and wash with water.Organic layer through anhydrous magnesium sulfate drying, is filtered then.Concentrated filtrate, and with residue through the silica gel column chromatography purification.Thereby from the part of hexane-ethyl acetate (3: 2) eluting, obtain the 4-[2 of 16mg, 6-two chloro-7-(2-chlorphenyl)-7H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester, and 4-[2-chloro-7-(2-the chlorphenyl)-1-methyl-6-oxo-6 that from the part of hexane-ethyl acetate (1: 9) eluting, obtains 10mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester.
(h) [7-(2-chlorphenyl)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base oxygen Base] the ethyl acetate trifluoro-acetate
With 4-[2-chloro-7-(2-chlorphenyl)-1-methyl-6-oxo-6 of 10mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester and 10mg glycolic ethyl ester be dissolved in the N-Methyl pyrrolidone of 0.2ml, and the 10mg sodium hydride added wherein.Mixture at room temperature stirred 2 hours.Reaction solution is dissolved in the ethyl acetate, and with mixture 1N salt pickling.Thereby obtain 4-[7-(2-chlorphenyl)-2-ethoxycarbonyl methoxy-1-methyl-6-oxo-6 of 24mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester.This chemical compound of 8mg is dissolved in the trifluoroacetic acid, and enriched mixture.Residue obtains the title compound of 2.11mg through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
MS?m/e(ESI)447(MH +-CF 3COOH)
Embodiment 4
2-[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base oxygen base] Phenylacetic acid methyl ester trifluoro-acetate
(a) [7-(2-butyne base)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2, the 2-diformazan The base propionic ester
With [1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2 of 1.871g, 2-dimethyl propylene acid esters is dissolved in the N of 30ml, in the dinethylformamide, and the 2-butyne base bromide of 1.5g potassium carbonate and 0.7ml is added wherein.Mixture at room temperature stirred spend the night.Reactant mixture is diluted with ethyl acetate, and water and the pickling of 1N salt.Organic layer through anhydrous magnesium sulfate drying, is filtered then.Solvent evaporated under reduced pressure, and with residue through the silica gel column chromatography purification.Thereby from the part of hexane-ethyl acetate (3: 2) eluting, obtain the title compound of 2.12g.
(b) 7-(2-butyne base)-1-methyl-3,7-dihydro purine-2,6-diketone
By used same procedure among the embodiment (1f), handle [7-(2-butyne base)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2,2-dimethyl propylene acid esters obtains title compound.
1H-NMR(CDCl 3)δ1.91(t，J＝2.4Hz，3H)3.39(s，3H)5.10(s，2H)7.93(s，1H)10.62(s，1H)。
(c) 4-[7-(2-butyne base)-1-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine -1-carboxylic acid tertiary butyl ester
By used same procedure among the embodiment (1e), handle 7-(2-butyne base)-1-methyl-3,7-dihydro purine-2, the 6-diketone obtains title compound.
1H-NMR(CDCl 3)δ1.48(s，9H)1.83(t，J＝2.4Hz，3H)3.37(s，3H)3.37-3.39(m，4H)3.58-3.60(m，4H)4.87(s，2H)9.68(s，1H)。
(d) 2-[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base The oxygen base] phenylacetic acid methyl ester trifluoro-acetate
With 4-[7-(2-butyne base)-1-methyl-2 of 8mg, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] the 2-bromophenyl methyl acetate of piperazine-1-carboxylic acid tertiary butyl ester and 10mg is dissolved in the N of 0.2ml, in the dinethylformamide, and the potassium carbonate of 10mg added wherein.Mixture is spent the night in 50 ℃ of stirrings.Ethyl acetate is joined in the reaction solution, and with mixture water and the pickling of 1N salt.Concentrate organic layer.Residue is dissolved in the trifluoroacetic acid, and enriched mixture.Residue obtains the title compound of 1.07mg through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
MS?m/e(ESI)451(MH +-CF 3COOH)
Embodiment 7
7-(2-butyne base)-2-cyclopentyloxy-1-methyl-8-(piperazine-1-yl)-1,7-dihydro purine-6-one trifluoro second Acid esters
In embodiment (4d), use bromocyclopentane to replace 2-bromophenyl methyl acetate, prepare title compound by same procedure used among the embodiment 4.
MS?m/e(ESI)371(MH +-CF 3COOH)
Embodiment 9
2-[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base oxygen base] Ethyl propionate
In embodiment (4d), use the 2 bromopropionic acid ethyl ester to replace 2-bromophenyl methyl acetate, prepare the trifluoro-acetate of title compound by same procedure used among the embodiment 4.(silica gel that its surface is modified with amino group: Fuji Silysia Chemical Ltd.NH-DM2035) chromatography carries out purification to this chemical compound by using NH-silica gel.Thereby from the part of ethyl acetate-methanol (20: 1) eluting, obtain title compound.
MS?m/e(ESI)404(MH +)
Embodiment 11
7-(2-butyne base)-2-methoxyl group-1-methyl-8-(piperazine-1-yl)-1,7-dihydro purine-6-one trifluoroacetic acid Ester
(a) 4-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purine-8-yl] piperazine-1- Carboxylic acid tertiary butyl ester (a-1), and 4-[7-(2-butyne base)-2,6-two chloro-7H-purine-8-yls] piperazine-1-carboxylic acid uncle Butyl ester (a-2)
With 4-[7-(2-butyne base)-1-methyl-2 of 5.127g, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 75ml phosphorus oxychloride, and then mixture spent the night in 120 ℃ of stirrings.Concentrated reaction solution, and residue is dissolved in the 50ml oxolane.This solution is poured in the suspension that contains 7g Bis(tert-butoxycarbonyl)oxide, 50ml oxolane, 100g sodium bicarbonate and 200ml water, and mixture was at room temperature stirred 1 hour.Reactant mixture is diluted with ethyl acetate, and mixture is washed with water.Organic layer through anhydrous magnesium sulfate drying, is filtered then.Concentrated filtrate, and with residue through the silica gel column chromatography purification.From the part of hexane-ethyl acetate (1: 1) eluting, obtain the 4-[7-(2-butyne base)-2 of 1.348g thus, 6-two chloro-7H-purine-8-yls] piperazine-1-carboxylic acid tertiary butyl ester [ 1H-NMR (CDCl 3) δ 1.50 (s, 9H) 1.87 (t, J=2.4Hz, 3H) 3.64 (m, 8H) 4.81 (q, J=2.4Hz, 2H)], and 4-[7-(2-butyne the base)-2-fluoro-1-methyl-6-oxo-6 that from the part of hexane-ethyl acetate (1: 9) eluting, obtains 1.238g, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester [ 1H-NMR (CDCl 3) δ 1.49 (and s, 9H) 1.83 (t, J=2.4Hz, 3H) 3.42-3.44 (m, 4H) 3.59-3.62 (m, 4H) 3.73 (s, 3H) 4.93 (q, J=2.4Hz, 2H)].
(b) 7-(2-butyne base)-2-methoxyl group-1-methyl-8-(piperazine-1-yl)-1,7-dihydro purine-6-one trifluoro Acetas
With 4-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6 of 8mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 0.2ml methanol, and the 10mg sodium hydride is added wherein.Mixture at room temperature stirred 1 hour.1N hydrochloric acid is joined in the reaction solution, and with the mixture ethyl acetate extraction.Concentrate organic layer, and residue is dissolved in the trifluoroacetic acid.Enriched mixture, and with residue through reversed phase high-performance liquid chromatography (use acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification, obtain the title compound of 1.72mg.
MS?m/e(ESI)317(MH +-CF 3COOH)
Embodiment 12
7-(2-butyne base)-2-ethyoxyl-1-methyl-8-(piperazine-1-yl)-1,7-dihydro purine-6-one
In embodiment (11b), use ethanol to replace methanol, prepare the trifluoro-acetate of title compound by same procedure used among the embodiment 11.This chemical compound carries out purification by the chromatography that uses NH-silica gel.Thereby from the part of ethyl acetate-methanol (20: 1) eluting, obtain title compound.
1H-NMR(CDCl 3)δ1.42(t，J＝7.2Hz，3H)1.82(t，J＝2.4Hz，3H)3.02-3.06(m，4H)3.40-3.42(m，4H)3.46(s，3H)4.51(q，J＝7.2Hz，2H)4.90(q，J＝2.4Hz，2H)。
MS?m/e(ESI)331(MH +)
Embodiment 13
[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base oxygen base] Ethyl acetate
Embodiment 14
[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base oxygen base] Acetic acid
By same procedure used among the embodiment 11, use the 2-hydroxyl ethyl acetate to replace Ethanol Treatment 4-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester, prepare [7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base oxygen base] ethyl acetate trifluoro-acetate and [7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base oxygen base] acetic acid trifluoro-acetate [MS m/e (ESI) 361 (MH +-CF 3COOH)].[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base oxygen base] ethyl acetate trifluoro-acetate is carried out purification by the chromatography that uses NH-silica gel.Thereby from the part of ethyl acetate-methanol (20: 1) eluting, obtain [7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base oxygen base] ethyl acetate [ 1H-NMR (CDCl 3) δ 1.29 (and t, J=7.2Hz, 3H) 1.83 (t, J=2.4Hz, 3H) 3.02-3.06 (m, 4H) 3.38-3.41 (m, 4H) 3.55 (s, 3H) 4.22 (q, J=7.2Hz, 2H) 4.90 (q, J=2.4Hz, 2H) 5.03 (s, 2H); MS m/e (ESI) 389 (MH +)].
Embodiment 16
1-[7-(2-butyne base-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base oxygen base] The cyclopropane carboxylic acid acetoacetic ester
In embodiment 13, use 1-hydroxyl cyclopropane carboxylic acid acetoacetic ester to replace the 2-hydroxyl ethyl acetate, prepare the trifluoro-acetate of title compound by same procedure used among the embodiment 13.This chemical compound carries out purification by the chromatography that uses NH-silica gel.Thereby from the part of ethyl acetate-methanol (20: 1) eluting, obtain title compound.
1H-NMR(CDCl 3)δ1.19(t，J＝7.2Hz，3H)1.39-1.42(m，2H)1.67-1.71(m，2H)1.83(t，J＝2.4Hz，3H)3.02-3.05(m，4H)3.37-3.40(m，4H)3.49(s，3H)4.14(q，J＝7.2Hz，2H)4.90(q，J＝2.4Hz，2H)
MS?m/e(ESI)415(MH +)
Embodiment 20
7-(2-butyne base)-1-methyl-2-phenoxy group-8-(piperazine-1-yl)-1,7-dihydro purine-6-one trifluoroacetic acid Ester
In embodiment 13, use phenol to replace the 2-hydroxyl ethyl acetate, prepare title compound by same procedure used among the embodiment 13.
MS?m/e(ESI)379(MH +-CF 3COOH)
Embodiment 22
7-(2-butyne base)-1,2-dimethyl-8-(piperazine-1-yl)-1,7-dihydro purine-6-one trifluoro-acetate
4-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6 with 8mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester and 2mg tetrakis triphenylphosphine palladium be dissolved in the 0.2ml diox, and 0.2ml methyl zinc chloride (1.5M tetrahydrofuran solution) added wherein.Mixture was stirred 0.5 hour in 50 ℃.Concentrated reaction solution, and residue is dissolved in the trifluoroacetic acid.Enriched mixture, and with residue through reversed phase high-performance liquid chromatography (use acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification, obtain the title compound of 4.56mg.
MS?m/e(ESI)301(MH +-CF 3COOH)
Embodiment 29
7-(2-butyne base)-1-methyl-2-dimethylamino-8-(piperazine-1-yl)-1,7-dihydro purine-6-one trifluoro Acetas
With 4-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6 of 8mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the aqueous solution of 40% dimethylamine of 0.2ml, and mixture stirred 5 hours in 80 ℃.Concentrated reaction solution, and residue is dissolved in the trifluoroacetic acid.Enriched mixture, and with residue through reversed phase high-performance liquid chromatography (use acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification, obtain the title compound of 6.95mg.
1H-NMR(CDCl 3)δ1.82(t，J＝2.4Hz，3H)2.83(s，6H)3.02-3.05(m，4H)3.39-3.42(m，4H)3.56(s，3H)4.90(d，J＝2.4Hz，2H)
MS?m/e(ESI)330(MH +-CF 3COOH)
Embodiment 41
7-(2-butyne base)-2-(2-ethoxyethyl group amino)-1-methyl-8-(piperazine-1-yl)-1,7-dihydro-purine -6-ketone trifluoro-acetate
With 4-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6 of 10mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 1-Methyl-2-Pyrrolidone of 0.15ml, and the 2-ethoxy ethyl amine of 20 μ l is added wherein.With mixture in 80 ℃ stir 12 hours after, by feeding the nitrogen concentrated reaction solution.The residue that generates is dissolved in the 0.40ml trifluoroacetic acid, and by feeding the nitrogen enriched mixture.Residue obtains the title compound of 6.95mg through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
MS?m/e(ESI)374(MH +-CF 3COOH)
Embodiment 53
(S)-and 1-[7-(2-butyne base)-1-methyl-6-hydrogen generation-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-yl] Pyrrolidine-2-carboxylic acid trifluoro-acetate
In embodiment 41, use L-proline tertiary butyl ester to replace the 2-ethoxy ethyl amine, prepare the title compound of 4.07mg by same procedure used among the embodiment 41.
MS?m/e(ESI)400(MH +-CF 3COOH)
Embodiment 63
(R)-and 1-[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-yl] Pyrrolidine-2-carboxylic acid trifluoro-acetate
4-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6 with 6mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 1-Methyl-2-Pyrrolidone of 0.15ml, and D-proline methyl ester hydrochloride and the 50 μ l triethylamines of 15mg are added wherein.After 12 hours, come concentrated reaction solution in 80 ℃ of stirrings at the mixture that generates by feeding nitrogen.Residue is dissolved in the solution of the 5N sodium hydrate aqueous solution that contains 0.20ml ethanol and 0.20ml.Mixture at room temperature stirs 5 hours, and concentrates by feeding nitrogen then.Residue is dissolved in the 0.40ml trifluoroacetic acid, and by feeding the nitrogen enriched mixture.Residue obtains the title compound of 3.42mg through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
MS?m/e(ESI)400(MH +-CF 3COOH)
Embodiment 64
2-[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base is amino] The propanoic acid trifluoro-acetate
In embodiment 63, use DL-methyl lactamine hydrochlorate to replace the D-proline methyl ester hydrochloride, prepare the title compound of 1.12mg by same procedure used among the embodiment 63.
MS?m/e(ESI)374(MH +-CF 3COOH)
Embodiment 68
[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base sulfane Base (sulfanyl)] the methyl acetate trifluoro-acetate
With 4-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6 of 6mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 1-Methyl-2-Pyrrolidone of 0.15ml, and 20 μ l methyl thioglycolates and 6mg potassium carbonate are added wherein.Mixture was at room temperature stirred 5 hours.Saturated aqueous ammonium chloride is joined in the reaction solution, and use the ethyl acetate extraction mixture.Concentrate organic layer, and residue is dissolved in the 0.40ml trifluoroacetic acid.Concentrate this solution by feeding nitrogen.Residue obtains the title compound of 4.83mg through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
MS?m/e(ESI)391(MH +-CF 3COOH)
Embodiment 73
7-(2-butyne base)-1-methyl-8-(piperazine-1-yl)-2-(pyridine-2-base sulfane base)-1,7-dihydro purine-6- The ketone trifluoro-acetate
In embodiment 68, use the 2-mercaptopyridine to replace methyl thioglycolate, prepare the title compound of 4.66mg by same procedure used among the embodiment 68.
MS?m/e(ESI)396(MH +-CF 3COOH)
Embodiment 76
7-(2-butyne base)-2-isopropyl sulfane base-1-methyl-8-(piperazine-1-yl)-1,7-dihydro purine-6-one three Ethyl fluoroacetate
With 4-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6 of 6mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 1-Methyl-2-Pyrrolidone of 0.15ml, and the sodium salt of propane-2-mercaptan of 15mg is added wherein.Mixture was at room temperature stirred 5 hours.Saturated ammonium chloride solution is joined in the reaction solution, and use the ethyl acetate extraction mixture.Concentrate organic layer, and residue is dissolved in the 0.40ml trifluoroacetic acid.Concentrate this solution by feeding nitrogen.Residue obtains the title compound of 4.56mg through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
MS?m/e(ESI)361(MH +-CF 3COOH)
Embodiment 79
[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base sulfane Base] the acetic acid trifluoro-acetate
With 4-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6 of 6mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the N-Methyl pyrrolidone of 0.15ml, and 20 μ l methyl thioglycolates and 6mg potassium carbonate are added wherein.After 5 hours, saturated aqueous ammonium chloride is joined in the reaction solution in stirring at room at mixture.Use the ethyl acetate extraction mixture.Concentrate organic layer.The residue that generates is dissolved in the solution of the 5N sodium hydrate aqueous solution that contains 0.20ml ethanol and 0.20ml.Mixture at room temperature stirred spend the night, and concentrate by feeding nitrogen then.Residue is dissolved in the 0.40ml trifluoroacetic acid, and concentrates this solution by feeding nitrogen.Residue is through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification, obtain 7-(2-butyne base)-2-sulfydryl-1-methyl-8-(piperazine-1-yl)-1 of 0.96mg, 7-dihydro purine-6-one trifluoro-acetate [MS m/e (ESI) 319 (MH +-CF 3And [7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base sulfane base] acetic acid trifluoro-acetate [MS m/e (ESI) 377 (MH of 0.61mg COOH)] +-CF 3COOH)].
Embodiment 82
7-(2-butyne base)-2-cyano group-1-methyl-8-(piperazine-1-yl)-1,7-dihydro purine-6-one trifluoro-acetate
With 4-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6 of 8mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the N-Methyl pyrrolidone of 0.2m1, and the 10mg Cyanogran. is added wherein.Mixture was stirred 1 hour in 50 ℃.Water is joined in the reactant mixture, and use the ethyl acetate extraction mixture.Concentrate organic layer, obtain 4-[7-(2-butyne base)-2-cyano group-1-methyl-6-oxo-6 of 14mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester.This chemical compound of 5mg is dissolved in the trifluoroacetic acid, and concentrates this solution.Residue obtains the title compound of 4.12mg through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
MS?m/e(ESI)312(MH +-CF 3COOH)
Embodiment 83
7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-Methanamide
(a) 4-[7-(2-butyne base)-2-carbamoyl-1-methyl-6-oxo-6,7-dihydro-1H-purine-8-yl] Piperazine-1-carboxylic acid tertiary butyl ester
With 4-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6 of 176mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the N-Methyl pyrrolidone of 2ml, and the 100mg Cyanogran. is added wherein.Mixture was stirred 0.5 hour in 50 ℃.Water is joined in the reactant mixture, and use the ethyl acetate extraction mixture.Concentrate organic layer, obtain 4-[7-(2-butyne base)-2-cyano group-1-methyl-6-oxo-6 of 170mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester.This chemical compound of 98mg is dissolved in 3ml oxolane and the 2ml methanol mixture, and 20% ammonia aqueous solution of 0.5ml and 30% aqueous hydrogen peroxide solution of 0.5ml are added wherein.Mixture at room temperature stirred spend the night.Ethyl acetate is joined in the reaction solution, and mixture is washed with water.Organic layer through anhydrous magnesium sulfate drying, is filtered then.Solvent evaporated under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby from the part of ethyl acetate-methanol-eluted fractions, prepare the title compound of 77mg.
1H-NMR(CDCl 3)δ1.49(s，9H)1.83(t，J＝1.2Hz，3H)3.42-3.49(m，4H)3.58-3.65(m，4H)3.95(s，3H)5.01(d，J＝2.4Hz，2H)5.54(br，1H)7.61(br，1H)
(b) 7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-formyl Amine
With 4-[7-(2-butyne base)-2-carbamoyl-1-methyl-6-oxo-6 of 77mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 1ml trifluoroacetic acid, and concentrated this solution.Residue is through using the chromatography purification of NH-silica gel.Thereby from the part of ethyl acetate-methanol (5: 1) eluting, prepare the title compound of 49mg.
1H-NMR(CDCl 3)δ1.83(t，J＝2.4Hz，3H)3.05-3.07(m，4H)3.45-3.48(m，4H)3.94(s，3H)4.98(s，2H)5.57(br，1H)7.65(br，1H)
Embodiment 86
7-(2-butyne base)-2-methoxyl group-1-(2-phenylethyl)-8-(piperazine-1-yl)-1,7-dihydro purine-6-one Hydrochlorate
(a) [7-benzyl-2,6-dioxo-1-(2-phenylethyl)-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2,2-two Methylpropionate
[7-benzyl-2, the 6-dioxo-1,2 that will contain 500mg, 6,7-tetrahydrochysene purine-3-yl] methyl 2, the N of the 2 bromoethyl benzene of 2-dimethyl propylene acid esters, 0.38ml, 390mg Anhydrous potassium carbonate and 5ml, the mixture of dinethylformamide stirred 2 hours in 50 ℃ in oil bath.With reactant mixture with the extraction of ethyl acetate and water, and with the organic layer water, and wash with saturated salt then.Organic liquid is through anhydrous magnesium sulfate drying, and concentrating under reduced pressure then.With residue ethyl acetate-hexane crystallization, obtain the title compound of 540mg.
1H-NMR(CDCl 3)δ1.19(s，9H)2.92-2.98(m，2H)4.19-4.25(m，2H)5.48(s，2H)6.11(s，2H)7.17-7.40(m，10H)7.54(s，1H)
(b) [7-(2-butyne base)-8-chloro-2,6-dioxo-1-(2-phenylethyl)-1,2,6,7-tetrahydrochysene purine-3-yl] Methyl 2,2-dimethyl propylene acid esters
[7-benzyl-2,6-dioxo-1-(2-phenylethyl)-1,2,6, the 7-tetrahydrochysene purine-3-yl] methyl 2 that will contain 540mg, the 10% palladium carbon of 2-dimethyl propylene acid esters, 50mg and the mixture of 8ml acetic acid at room temperature stir under hydrogen and spend the night.Filter reaction mixture, and concentrating under reduced pressure then obtain the 410mg residue.
With the N of 1-bromo-2-butyne, 300mg Anhydrous potassium carbonate and the 5ml of whole residues and 0.15ml, dinethylformamide mixes.Mixture at room temperature stirred 2 hours.Reaction solution extracts with ethyl acetate and water.The organic layer water is also washed with saturated salt then.Organic liquid is through anhydrous magnesium sulfate drying, and concentrating under reduced pressure, obtains the 470mg residue.
With the N-chloro-succinimide of whole residues and 180mg and the N of 5ml, dinethylformamide mixes.Mixture at room temperature stirred 2 hours.After the 1M sodium thiosulfate solution with 0.5ml joins in the reaction solution, with ethyl acetate and water extraction mixture.With the organic layer water, and wash with saturated salt then.Organic liquid is through anhydrous magnesium sulfate drying, and concentrating under reduced pressure then.By using ethyl acetate-hexane crystallization to prepare the title compound of 380mg.
1H-NMR(CDCl 3)δ1.21(s，9H)1.83(t，J＝2Hz，3H)2.92-2.98(m，2H)4.19-4.25(m，2H)5.11(q，J＝2Hz，2H)6.05(s，2H)7.18-7.32(m，5H)
(c) 4-[7-(2-butyne base)-2,6-dioxo-1-(2-phenylethyl)-2,3,6,7-tetrahydrochysene-1H-purine-8- Base] piperazine-1-carboxylic acid tertiary butyl ester
[the 7-(2-butyne base)-8-chloro-2 that will contain 380mg, 6-dioxo-1-(2-phenylethyl)-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2, the mixture of the N-Methyl pyrrolidone of the piperazine of 2-dimethyl propylene acid esters, 460mg-1-carboxylic acid tertiary butyl ester and 0.5ml stirred 15 minutes in 150 ℃ in oil bath.Reactant mixture is with the extraction of ethyl acetate and water, and with the organic layer water, and wash with saturated salt then.With organic layer through anhydrous magnesium sulfate drying, and concentrating under reduced pressure then.Residue is dissolved in the ethyl acetate/hexane (1/1).By a small amount of silica gel filtering solution, and use ethyl acetate/hexane (1/1) to wash then.Filtrate is mixed with cleaning mixture.The concentrating under reduced pressure mixed solution obtains the residue of 570mg.
With whole residues and 5ml oxolane and 2.5ml methanol mixed.The 33mg sodium hydride is joined in the mixture, and the mixture that generates was at room temperature stirred 30 minutes.The 1N hydrochloric acid of 1ml is joined in the reaction solution, and then with ethyl acetate and water extraction mixture, then water, and wash with saturated salt then.Organic liquid is through anhydrous magnesium sulfate drying, and concentrating under reduced pressure, obtains the title compound of 350mg.
1H-NMR(CDCl 3)δ1.50(s，9H)1.85(t，J＝2Hz，3H)2.91-2.98(m，2H)3.37(br.s，4H)3.56-3.62(m，4H)4.15-4.22(m，2H)4.87(q，J＝2Hz，2H)7.18-7.35(m，5H)
(d) 4-[7-(2-butyne base)-2-chloro-6-oxo-1-(2-phenylethyl)-6,7-dihydro-1H-purine-8-yl] Piperazine-1-carboxylic acid tertiary butyl ester
Heating contains the 4-[7-(2-butyne base)-2 of 290mg, 6-dioxo-1-(2-phenylethyl)-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] mixture of piperazine-1-carboxylic acid tertiary butyl ester and 4ml phosphorus oxychloride and in oil bath, stirring 8 hours in 120 ℃.The concentrating under reduced pressure reaction solution, and residue is dissolved in the 5ml oxolane.This drips of solution is added to contains in 250mg Bis(tert-butoxycarbonyl)oxide, 10ml saturated sodium bicarbonate aqueous solution and the 10ml tetrahydrofuran compound, stir the mixture simultaneously and with ice-cooled.Mixture is placed room temperature following 4 hours, and use ethyl acetate extraction then.The organic layer water, then with saturated salt washing, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure then.Residue is through using the silica gel column chromatography purification of 30-50% ethyl acetate/hexane.Then, the reversed-phase column chromatography method of this material through using the 50-100% methanol is further purified, obtains the title compound of 60mg.
1H-NMR(CDCl 3)δ1.49(s，9H)1.84(t，J＝2Hz，3H)3.10-3.16(m，2H)3.40-3.46(m，2H)3.57-3.63(m，4H)4.42-4.49(m，4H)4.94(q，J＝2Hz，2H)7.21-7.34(m，5H)
(e) 7-(2-butyne base)-2-methoxyl group-1-(2-phenylethyl)-8-(piperazine-1-yl)-1,7-dihydro purine-6- Keto hydrochloride
With 10mg sodium hydride (60%; Buttery) join 4-[7-(2-butyne the base)-2-chloro-6-oxo-1-(2-phenylethyl)-6 that contains 7mg, 7-dihydro-1H-purine-8-yl] in piperazine-1-carboxylic acid tertiary butyl ester and the 0.5ml methanol mixture.Mixture was at room temperature stirred 20 minutes.Water is joined in the reaction solution.Use the ethyl acetate extraction mixture.With the organic layer water, also then with the saturated salt washing, and concentrate.The 0.5ml trifluoroacetic acid is joined in the residue.Mixture at room temperature stirs 30 minutes, and concentrates then.Residue through using the reversed-phase column chromatography method purification of 20-80% methanol (containing 0.1% concentrated hydrochloric acid), is obtained the title compound of 4.3mg.
1H-NMR(DMSO-d6)δ1.80(br.s，3H)2.85(t，J＝7Hz，2H)3.28(br.s，4H)3.48-3.54(m，4H)3.83(s，3H)4.15(t，J＝7Hz，2H)4.97(br.s，2H)7.16-7.24(m，3H)7.29(t，J＝8Hz，2H)9.08(br.s，2H)
Embodiment 88
[7-(2-butyne base)-6-oxo-1-(2-phenylethyl)-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2- Base sulfane base] the methyl acetate hydrochlorate
In embodiment 86 (e), use methyl thioglycolate to replace methanol and use potassium carbonate, by same procedure synthesising title compound used among the embodiment 86 as alkali.
1H-NMR(DMSO-d6)δ1.80(s，3H)2.96(t，J＝8Hz，2H)3.29(br.s，4H)3.50-3.56(m，4H)3.68(s，3H)4.16(s，2H)4.23(t，J＝8Hz，2H)4.99(s，2H)7.24-7.38(m，5H)8.96(br.s，2H)
Embodiment 95
7-(2-butyne base)-2-chloro-8-(piperazine-1-yl)-1,7-dihydro purine-6-one trifluoro-acetate
(a) 4-[7-(2-butyne base)-2-chloro-6-oxo-6,7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid uncle fourth The base ester
The 4-[7-(2-butyne base)-2 that will contain 1.0g, 6-two chloro-7H-purine-8-yls] mixture of piperazine-1-carboxylic acid tertiary butyl ester, 580mg sodium acetate and 10ml dimethyl sulfoxine stirred 24 hours in 80 ℃ in oil bath.Reaction solution extracts with ethyl acetate and water.With the organic layer water, also then with the saturated salt washing, then through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Residue is through using the silica gel column chromatography purification of 50-70% ethyl acetate/hexane, and with ethyl acetate-hexane crystallization, obtains the title compound of 800mg.
1H-NMR(CDCl 3)δl.49(s，9H)1.83(t，J＝2Hz，3H)3.44(br.s，4H)3.56-3.63(m，4H)4.94(q，J＝2Hz，2H)
(b) 7-(2-butyne base)-2-chloro-8-(piperazine-1-yl)-1,7-dihydro purine-6-one trifluoro-acetateWith 4-[7-(2-butyne base)-2-chloro-6-oxo-6 of 8mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the trifluoroacetic acid, and concentrated this solution.Residue obtains the title compound of 3.45mg through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
MS?m/e(ESI)307(MH +-CF 3COOH)
Embodiment 96
2-[7-(2-butyne base)-2-dimethylamino-6-oxo-8-(piperazine-1-yl)-6,7-dihydro purine-1-base Methyl] the benzonitrile hydrochlorate
(a) 4-[7-(2-butyne base)-2-chloro-1-(2-cyano group benzyl)-6-oxo-6,7-dihydro-1H-purine-8-yl] Piperazine-1-carboxylic acid tertiary butyl ester
4-[7-(2-butyne the base)-2-chloro-6-oxo-6 that will contain 100mg, 7-dihydro-1H-purine-8-yl] N of 2-cyano-benzyl bromide, 68mg Anhydrous potassium carbonate and 1ml of piperazine-1-carboxylic acid tertiary butyl ester, 60mg, the mixture of dinethylformamide at room temperature stirred 4 hours.Ethyl acetate/hexane (1/1) and water are joined in the reaction solution.Remove by filter insoluble matter.Filtrate is used ethyl acetate extraction.With the organic layer water, and then with saturated salt washing, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure then.Residue obtains the title compound of 50mg through using the silica gel column chromatography purification of 30-50% ethyl acetate/hexane.
1H-NMR(CDCl 3)δ1.49(s，9H)1.83(t，J＝2Hz，3H)3.43-3.49(m，4H)3.58-3.64(m，4H)4.95(q，J＝2Hz，2H)5.72(s，2H)7.06(d，J＝8Hz，1H)7.39(t，J＝8Hz，1H)7.51(t，J＝8Hz，1H)7.71(d，J＝8Hz，1H)
(b) 4-[7-(2-butyne base)-1-(2-cyano group benzyl)-2-dimethylamino-6-oxo-6,7-dihydro-1H-is fast Purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester
4-[7-(2-butyne base)-2-chloro-1-(2-cyano group the benzyl)-6-oxo-6 that will contain 8mg, 7-dihydro-1H-purine-8-yl] aqueous solution of 50% dimethylamine of piperazine-1-carboxylic acid tertiary butyl ester, 20 μ l and the N of 0.2ml, the mixture of dinethylformamide at room temperature stirred 2 hours.Reaction solution extracts with ethyl acetate and water.Organic layer water and with saturated salt washing, and concentrate.Residue is separated by the silica gel thin-layer chromatography of using 70% ethyl acetate/hexane, obtain the title compound of 6.5mg.
1H-NMR(CDCl 3)δ1.50(s，9H)1.81(t，J＝2Hz，3H)2.73(s，6H)3.38-3.45(m，4H)3.56-3.64(m，4H)4.91，(q，J＝2Hz，2H)5.55(s，2H)7.07(d，J＝8Hz，1H)7.32(t，J＝8Hz，1H)7.46，(t，J＝8Hz，1H)7.65(d，J＝8Hz，1H)
(c) 2-[7-(2-butyne base)-2-dimethylamino-6-oxo-8-(piperazine-1-yl)-6,7-dihydro purine-1- Ylmethyl] the benzonitrile hydrochlorate
With 4-[7-(2-butyne base)-1-(2-cyano group benzyl)-2-dimethylamino-6-oxo-6 of 6.5mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 0.5ml trifluoroacetic acid, and mixture at room temperature left standstill 20 minutes.Concentrated reaction solution, and, obtain the title compound of 6.4mg with the reversed-phase column chromatography method purification of residue through use 20-80% methanol (containing 0.1% concentrated hydrochloric acid).
1H-NMR(DMSO-d6)δ1.76(s，3H)2.69(s，6H)3.28(br.s，4H)3.51(br.s，4H)4.91(s，2H)5.40(s，2H)7.04(d，J＝8Hz，1H)7.43(t，J＝8Hz，1H)7.60(t，J＝8Hz，1H)7.83(d，J＝8Hz，1H)8.90(br.s，2H)
Embodiment 98
2-[7-(2-butyne base)-2-methoxyl group-6-oxo-8-(piperazine-1-yl)-6,7-dihydro purine-1-ylmethyl] The benzonitrile hydrochlorate
In embodiment 96 (b), use methanol to replace dimethylamine and use Anhydrous potassium carbonate, by same procedure synthesising title compound used among the embodiment 96 as alkali.
1H-NMR(DMSO-d6)δ1.79(s，3H)3.28(br.s，4H)3.48-3.56(m，4H)3.91(s，3H)4.97(s，2H)5.32(s，2H)7.19(d，J＝8Hz，1H)7.48(t，J＝8Hz，1H)7.63(t，J＝8Hz，1H)7.87(d，J＝8Hz，1H)9.05(br.s，2H)
Embodiment 109
7-benzyl-1-methyl-8-(piperazine-1-yl)-1,7-dihydro purine-6-one trifluoro-acetate
(a) 7-benzyl-1,7-dihydro purine-6-one
The 18.23g inosine is dissolved in the 90ml dimethyl sulfoxine, and the 16ml benzyl bromide a-bromotoluene is added wherein.Mixture at room temperature stirred spend the night.Reaction solution is poured in the 3L ethyl acetate.Remove the supernatant of generation and sedimentary grease is dissolved in 10% hydrochloric acid (135ml).With solution in 70 ℃ of heated and stirred 4 hours.This solution is cooled to room temperature, and to use the 5N sodium hydrate aqueous solution to be neutralized to pH then be 7.Filter the solid and the drying of collecting precipitation, obtain the title compound of 12.748g.
(b) 4-(7-benzyl-6-oxo-6,7-dihydro-1H-purine-8-yl) piperazine-1-carboxylic acid tertiary butyl ester
With the 7-benzyl-1 of 12.748g, 7-dihydro purine-6-one is dissolved in the N of 150ml, in the dinethylformamide, and the N-chloro-succinimide of 7.9g is added wherein.Reaction solution stirs and spends the night, and dilutes with ethyl acetate then.With this solution with water and the pickling of 1N salt, and through anhydrous magnesium sulfate drying.Filtering solution, and concentrated filtrate obtain 7-benzyl-8-chloro-1 of 6.103g, 7-dihydro purine-6-one.This chemical compound is mixed with 20g piperazine-1-carboxylic acid tertiary butyl ester, and mixture is heated down in 150 ℃.Stir after 1 hour, reactant mixture is mixed with ethyl acetate and water and distribute.Organic layer 1N salt pickling, and through anhydrous magnesium sulfate drying.After the filtration, concentrated filtrate.Residue is through the silica gel column chromatography purification.Thereby from the part of ethyl acetate-methanol (10: 1) eluting, prepare the title compound of 1.539g.
1H-NMR(CDCl 3)δ1.39(s，9H)3.07-3.10(m，4H)3.35-3.39(m，4H)5.44(s，2H)7.16-7.18(m，2H)7.22-7.32(m，3H)7.91(s，1H)12.18(s，1H)
(c) 7-benzyl-1-methyl-8-(piperazine-1-yl)-1,7-dihydro purine-6-one trifluoro-acetate
4-(7-benzyl-6-oxo-6,7-dihydro-1H-purine-8-yl) piperazine-1-carboxylic acid tertiary butyl ester of 15mg is dissolved in the N of 1ml, in the dinethylformamide, and 10mg sodium hydride and 10 μ l iodomethane is added wherein.Mixture was at room temperature stirred 3 days, add ethyl acetate and water then, separates two.Concentrate organic layer, and residue is dissolved in the trifluoroacetic acid.Concentrate this solution.Residue obtains the title compound of 4.31mg through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
MS?m/e(ESI)325(MH +-CF 3COOH)
Embodiment 115
3-(2-butyne base)-5-methyl-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone trifluoro also Acetas
(a) 2-bromo-3-(2-butyne base)-5-cyano group-3H-imidazoles-4-carboxylic acid, ethyl ester
4.56ml sulphuric acid is joined the 2-bromo-1H-imidazoles-4 that 170ml contains 16.80g, in the ethanol of 5-dintrile [CASNo.50847-09-1], and with mixture heated backflow 48 hours.Cool off this solution, and then 500ml ethyl acetate and 200ml water are added wherein.Organic layer through anhydrous magnesium sulfate drying, is filtered and concentrating under reduced pressure.Residue is dissolved in N, in the dinethylformamide, and the 2-butyne base bromide of 14.1g potassium carbonate and 8.6ml is added wherein.With mixture stirring at room 18 hours.The 500ml ethyl acetate is joined in the solution, and with mixture with 300ml water, and give a baby a bath on the third day after its birth inferior then with the 300ml saturated sodium-chloride water solution.Then with this solution through anhydrous magnesium sulfate drying, and filter.Concentrating under reduced pressure filtrate.Residue is through the silica gel column chromatography purification.Thereby from the part of hexane-ethyl acetate (9: 1) eluting, prepare the title compound of 4.09g.
1H-NMR(CDCl 3)δ1.43(t，J＝7.2Hz，3H)1.81(s，3H)4.47(q，J＝7.2Hz，2H)5.16(s，2H)
(h) d-[1-(2-butyne base)-4-cyano group-5-ethyoxyl carboxyl-1H-imidazoles-2-yl] piperazine-1-carboxylic acid uncle fourth The base ester
2-bromo-3-(2-butyne base)-5-cyano group-3H-imidazoles-4-carboxylic acid, ethyl ester of 4.09g is mixed with 7.70g piperazine-1-carboxylic acid tertiary butyl ester, and with mixture in 150 ℃ of following heated and stirred 50 minutes.Reactant mixture is dissolved in the toluene.With mixture through the silica gel column chromatography purification.Therefore from the part of hexane-ethyl acetate (2: 1) eluting, prepare the title compound of 4.47g.
1H-NMR(CDCl 3)δ1.43(t，J＝7.2Hz，3H)1.47(s，9H)1.82(t，J＝2.3Hz，3H)3.08-3.13(m，4H)3.57-3.61(m，4H)4.44(q，J＝7.2Hz，2H)4.89(q，J＝2.3Hz，2H)
(c) 4-[1-(2-butyne base)-5-ethoxy carbonyl-4-thiocarbamoyl-1H-imidazoles-2-yl] piperazine -1-carboxylic acid tertiary butyl ester
50% ammonium sulfide solution of 5ml is joined 4-[1-(2-butyne the base)-4-cyano group-5-ethoxy carbonyl-1H-imidazoles-2-yl that contains 0.80g] in the 20-ml alcoholic solution of piperazine-1-carboxylic acid tertiary butyl ester, and with mixture in 60 ℃ of heating 14 hours.100ml ethyl acetate and 50ml water are joined in the mixture, and organic layer is washed with 50ml water and 50ml saturated sodium-chloride water solution successively.Reaction solution filters then through anhydrous magnesium sulfate drying.Concentrating under reduced pressure filtrate.Residue is through the silica gel column chromatography purification.Therefore from the part of hexane-ethyl acetate (3: 2) eluting, prepare the title compound of 0.58g.
1H-NMR(CDCl 3)δ1.43(t，J＝7.2Hz，3H)1.48(s，9H)1.82(t，J＝2.3Hz，3H)3.12-3.16(m，4H)3.54-3.59(m，4H)4.44(q，J＝7.2Hz，2H)4.89(q，J＝2.3Hz，2H)7.41(br.s，1H)8.88(br.s，1H)
(d) 4-[1-(2-butyne base)-5-ethoxy carbonyl-4-methyl sulfane base imino group (carbonimidovl)-and 1H-imidazoles-2-yl] piperazine-1-carboxylic acid tertiary butyl ester
0.235 trimethyl oxygen tetrafluoroborate is joined 4-[1-(2-butyne base)-5-ethoxy carbonyl-4-thiocarbamoyl-1H-imidazoles-2-yl of 0.58g] in the 20-ml dichloromethane solution of piperazine-1-carboxylic acid tertiary butyl ester, and with mixture stirring at room 18 hours.The 50ml dichloromethane is joined in the solution, and mixture is washed with the saturated sodium bicarbonate aqueous solution of 20ml.Mixture is through anhydrous magnesium sulfate drying, and concentrating under reduced pressure, obtains the title compound of 0.55g.
1H-NMR(CDCl 3)δ1.41(t，J＝7.2Hz，3H)1.47(s，9H)1.81(t，J＝2.3Hz，3H)2.39(s，3H)3.12-3.16(m，4H)3.56-3.59(m，4H)4.42(q，J＝7.2Hz，2H)4.80(q，J＝2.3Hz，2H)
(e) 4-[1-(2-butyne base)-5-ethoxy carbonyl-4-methyl sulfane base carbonyl-1H-imidazoles-2-yl] piperazine -1-carboxylic acid tertiary butyl ester
The 2N aqueous hydrochloric acid solution of 5ml is joined 4-[1-(2-butyne base)-5-ethoxy carbonyl-4-methyl sulfane base imino group-1H-imidazoles-2-yl of 0.55g] in the 30-ml alcoholic solution of piperazine-1-carboxylic acid tertiary butyl ester, and with mixture in 60 ℃ of heating 5 hours.Behind the concentrating under reduced pressure reaction solution, 25ml ethyl acetate and 1N sodium hydroxide solution are added wherein.With water layer 25ml ethyl acetate extraction, and organic layer is merged together.Mixture is washed with the 10ml saturated sodium-chloride water solution of the 1N sodium hydroxide solution that contains 1ml, and through anhydrous magnesium sulfate drying.Filtering solution and concentrating under reduced pressure filtrate.Residue is dissolved in the 10ml dichloromethane, and 0.10ml triethylamine and 0.256g Bis(tert-butoxycarbonyl)oxide are added wherein.Mixture at room temperature stirs 15 hours, and then the 25ml ethyl acetate is added wherein.Mixture is washed with the 0.1N hydrochloric acid of 10ml, saturated sodium bicarbonate aqueous solution and the 10ml saturated sodium-chloride water solution of 10ml respectively, and then through anhydrous magnesium sulfate drying.This solution of concentrating under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby from the part of hexane-ethyl acetate (4: 1) eluting, prepare the title compound of 0.15g.
1H-NMR(CDCl 3)δ1.43(t，J＝7.1Hz，3H)1.48(s，9H)1.81(t，J＝2.3Hz，3H)2.40(s，3H)3.16-3.20(m，4H)3.55-3.59(m，4H)4.35(q，J＝7.1Hz，2H)4.80(q，J＝2.3Hz，2H)
(f) 4-[1-(2-butyne base)-5-ethoxy carbonyl-4-hydroxymethyl-1H-imidazoles-2-yl] piperazine-1-carboxylic acid Tertiary butyl ester
Under 0 ℃, 0.187g mercuric acetate (II) and 0.090 sodium borohydride are joined the 4-[1-that contains 0.265g (2-butyne base)-5-ethoxy carbonyl-4-methyl sulfane base carbonyl-1H-imidazoles-2-yl of 8ml] in the alcoholic solution of piperazine-1-carboxylic acid tertiary butyl ester, and mixture at room temperature stirred 4 hours.After joining 0.187g mercuric acetate (II) and 0.090 sodium borohydride in the solution, mixture was at room temperature stirred 15 hours.The 0.5N hydrochloric acid of 100ml ethyl acetate and 50ml is joined in the solution, and organic layer is washed with 50ml water and 50ml saturated sodium-chloride water solution successively.Mixture is through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Residue is through the silica gel column chromatography purification.From the part of hexane-ethyl acetate (4: 1) eluting, collect the starting material of 0.172g.From the part of hexane-ethyl acetate (1: 4) eluting, prepare the title compound of 0.061g then.
1H-NMR(CDCl 3)δ1.42(t，J＝7.1Hz，3H)1.48(s，9H)1.81(t，J＝2.3Hz，3H)3.17-3.21(m，4H)3.41(t，J＝4.8Hz，1H)3.56-3.60(m，4H)4.36(q，J＝7.1Hz，2H)4.75(d，J＝4.8Hz，2H)4.81(q，J＝2.3Hz，2H)
(g) 4-[1-(2-butyne base)-5-ethoxy carbonyl-4-formoxyl-1H-imidazoles-2-yl] piperazine-1-carboxylic acid uncle Butyl ester
0.120g manganese dioxide is joined 4-[1-(2-butyne base)-5-ethoxy carbonyl-4-hydroxymethyl-1H-imidazoles-2-yl of 0.061g] in the 2-ml dichloromethane solution of piperazine-1-carboxylic acid tertiary butyl ester, and mixture at room temperature stirred 15 hours.Reaction solution filters by Celite (kieselguhr), and concentrating under reduced pressure filtrate.Residue is through the silica gel column chromatography purification.Thereby from the part of hexane-ethyl acetate (7: 3) eluting, prepare the title compound of 0.055g.
1H-NMR(CDCl 3)δ1.42(t，J＝7.1Hz，3H)1.48(s，9H)1.82(t，J＝2.3Hz，3H)3.23-3.26(m，4H)3.55-3.59(m，4H)4.45(q，J＝7.1Hz，2H)4.89(q，J＝2.3Hz，2H)10.36(s，1H)
(h) 4-[1-(2-butyne base)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl] Piperazine-1-carboxylic acid tertiary butyl ester
The 0.05ml methylhydrazine is joined 4-[1-(2-butyne base)-5-ethoxy carbonyl-4-formoxyl-1H-imidazoles-2-yl of 0.055g] in the 2.5-ml alcoholic solution of piperazine-1-carboxylic acid tertiary butyl ester.Mixture was stirred 15 hours in 80 ℃, and then in 130 ℃ of heating 14 hours.The concentrating under reduced pressure reaction solution.Then with residue through the silica gel column chromatography purification.Thereby from the part of hexane-ethyl acetate (1: 1) eluting, prepare the title compound of 0.035g.
1H-NMR(CDCl 3)δ1.52(s，9H)1.83(t，J＝2.3Hz，3H)3.38-3.42(m，4H)3.61-3.64(m，4H)3.85(s，3H)5.09(q，J＝2.3Hz，2H)8.13(s，1H)
MS?m/e(ESI)387.4(MH +)
(i) 3-(2-butyne base)-5-methyl-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone three also Ethyl fluoroacetate
The 0.4ml trifluoroacetic acid is joined 4-[1-(2-butyne base)-6-methyl-7-oxo-6 of 0.0351g, 7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl] in the 0.4-ml dichloromethane solution of piperazine-1-carboxylic acid tertiary butyl ester, and mixture at room temperature stirred 1 hour.Concentrated solvent.Residue obtains the title compound of 0.0295g through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
1H-NMR(CD 3OD)δ1.83(t，J＝2.3Hz，3H)3.45-3.49(m，4H)3.65-3.69(m，4H)3.83(s，3H)5.15(q，J＝2.3Hz，2H)8.20(s，1H)
MS?m/e(ESI)287.09(MH +-CF 3COOH)
Embodiment 116
5-benzyloxy methyl-3-(2-butyne base)-2-(piperazine-1-yl)-3, the 5-dihydro-imidazol-is [4,5-d] pyridazine also -4-ketone trifluoro-acetate
(a) 5-benzyloxy methyl-4-oxo-4,5-glyoxalidine be [4,5-d] pyridazine-1-sulfonic acid dimethyl acyl also Amine
N with 2.08g triethylamine, 2.80g; the 5-benzyloxy Methylimidazole. that the 4-dimethylaminopyridine of N-dimethylamino sulfonyl chlorine and 0.22g joins 3.04g is (methylimmidazo) [4 also; 5-d] (R.Paul Gagnier in the dichloromethane solution of 50ml of pyridazine 4-ketone [CAS NO.82137-50-6]; Michael J.Halat; and Brian A.Otter Journal of Heterocyclic Chemistry, 21, p481; 1984), and with mixture heated refluxed 4 hours.The 250ml ethyl acetate is joined in the solution, and mixture is washed with 50ml aqueous solution, 50ml saturated sodium bicarbonate aqueous solution and the 50ml saturated sodium-chloride water solution of 1N hydrochloric acid respectively.Mixture is through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby from the part of hexane-ethyl acetate (2: 3) eluting, prepare the title compound of 2.86g.
1H-NMR(CDCl 3)δ2.98(s，6H)4.77(s，2H)5.74(s，2H)7.30-7.39(m，5H)8.21(s，1H)8.46(s，1H)
(b) 5-benzyloxy methyl-2-chloro-4-oxo-4, the 5-glyoxalidine is [4,5-d] pyridazine-1-sulfonic acid diformazan also The base amide
Under nitrogen in-78 ℃, the n-BuLi (2.0M cyclohexane solution) of 5.3ml is joined 5-benzyloxy methyl-4-oxo-4 of 3.34g, 5-glyoxalidine also [4,5-d] in the 150-ml tetrahydrofuran solution of pyridazine-1-sulfonic acid dimethylformamide, and mixture stirred 1 hour down in-78 ℃.Tetrahydrofuran solution with the 3.26g hexachlorethane of 20ml joins in this solution then.Mixture is warmed to room temperature.5% aqueous ammonium chloride solution of 25ml is joined in the solution, and with mixture 50ml ethyl acetate extraction.Organic layer is washed with 25ml water and 25ml saturated sodium-chloride water solution successively, and then through anhydrous magnesium sulfate drying.The concentrating under reduced pressure organic liquid.Residue is through the silica gel column chromatography purification.Thereby from the part of hexane-ethyl acetate (2: 3) eluting, prepare the title compound of 2.31g.
1H-NMR(CDCl 3)δ3.12(s，6H)4.77(s，2H)5.70(s，2H)7.30-7.39(m，5H)8.48(s，1H)
(c) 4-(6-benzyloxy methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl) piperazine -1-carboxylic acid tertiary butyl ester
Under nitrogen, will contain 5-benzyloxy methyl-2-chloro-4-oxo-4 of 2.31g, the 5-glyoxalidine also the mixture of [4,5-d] pyridazine-1-sulfonic acid dimethylformamide and 4.49g piperazine-1-carboxylic acid tertiary butyl ester in 150 ℃ of heating 2.5 hours.Residue is through the silica gel column chromatography purification.Thereby from the part of eluent ethyl acetate, prepare the title compound of 1.94g.
1H-NMR(CDCl 3)δ3.54-3.58(m，4H)3.71-3.75(m，4H)4.68(s，2H)5.65(s，2H)7.25-7.35(m，5H)8.21(s，1H)12.58(br.s，1H)
(d) 4-[6-benzyloxy methyl isophthalic acid-(2-butyne base)-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] is rattled away Piperazine-2-yl] piperazine-1-carboxylic acid tertiary butyl ester
The 2-butyne base bromine of 0.74g potassium carbonate and 0.078g is joined 4-(the 6-benzyloxy methyl-7-oxo-6 of 0.216g, 7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl) N of 20-ml of piperazine-1-carboxylic acid tertiary butyl ester, in the dinethylformamide solution, and mixture at room temperature stirred l 6 hours.Then the 50ml ethyl acetate is joined in the solution.Organic layer with 20ml water, and give a baby a bath on the third day after its birth inferior then with the 10ml saturated sodium-chloride water solution.This solution is through anhydrous magnesium sulfate drying, and concentrating under reduced pressure then.Residue is through the silica gel column chromatography purification.Thereby from the part of hexane-ethyl acetate (3: 2) eluting, prepare the title compound of 0.139g.
1H-NMR(CDCl 3)δ1.50(s，9H)1.86(t，J＝2.3Hz，3H)3.38-3.44(m，4H)3.61-3.66(m，4H)4.72(s，2H)5.10(q，J＝2.3Hz，2H)5.65(s，2H)7.25-7.38(m，5H)8.18(s，1H)
(e) 5-benzyloxy methyl-3-(2-butyne base)-2-(piperazine-1-yl)-3,5-glyoxalidine also [4,5-d] is rattled away Piperazine-4-ketone trifluoro-acetate
By used same procedure among the embodiment 115 (i), by handling 4-[6-benzyloxy methyl isophthalic acid-(2-butyne base)-7-oxo-6 of 0.0073g, 7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl] piperazine-1-carboxylic acid tertiary butyl ester and purified product, obtain the title compound of 0.0043g.
1H-NMR(CD 3OD)δ1.83(t，J＝2.3Hz，2H)3.45-3.49(m，4H)3.65-3.69(m，4H)4.69(s，2H)5.15(q，J＝2.3Hz，2H)5.64(s，2H)7.17-7.32(m，5H)8.20(s，1H)
MS?m/e(ESI)393.28(MH +-CF 3COOH)
Embodiment 117
3 -(2-butyne base)-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone trifluoro-acetate also
Under nitrogen, 4-[6-benzyloxy methyl isophthalic acid-(2-butyne base)-7-oxo-6 with 0.123g, 7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl] the 8ml dichloromethane solution of piperazine-1-carboxylic acid tertiary butyl ester is cooled to-78 ℃, and 1.9ml boron chloride (1.0M dichloromethane solution) added wherein.Mixture was stirred 5 hours down in-78 ℃, and 1: 1 the methylene chloride-methanol mixed solvent of 10ml is added wherein.Mixture was stirred 2 hours down in-78 ℃, and make it to be warmed to room temperature then.The concentrating under reduced pressure solvent, and with the adding of 10ml methanol wherein.Then with solution concentrating under reduced pressure once more.Residue is dissolved in the 3ml pyridine, and mixture heated was refluxed 2 hours.This solution decompression of 0.3ml is concentrated.Residue obtains the title compound of 0.005g through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
1H-NMR(CD 3OD)δ1.83(t，J＝2.3Hz，3H)3.45-3.49(m，4H)3.65-3.69(m，4H)5.16(q，J＝2.3Hz，2H)8.21(s，1H)
MS?m/e(ESI)273.16(MH +-CF 3COOH)
Embodiment 118
2 -[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base oxygen base] The benzamide hydrochlorate
(a) 4-[7-(2-butyne base)-2-(2-carbamyl phenoxyl)-1-methyl-6-oxo-6,7-dihydro-1H- Purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester
With 4-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6 of 200mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 1-Methyl-2-Pyrrolidone of 2.0ml, and 85mg salicylamide and 129mg potassium carbonate are added wherein.Mixture was stirred 2 hours in 100 ℃.After reactant mixture is cooled to room temperature, 5.0ml water is added wherein.After 1 hour, filter and collect white precipitate in stirring at room at mixture.The white solid water and the ether that generate are washed, obtained the title compound (89%) of 221mg.
1H-NMR(DMSO-d6)δ1.43(s，9H)1.79(t，J＝2.5Hz，3H)3.23-3.27(m，4H)3.36(s，3H)3.48-3.52(m，4H)4.95(q，2.5Hz，2H)6.59(td，J＝8.0，1.0Hz，1H)6.63(dd，J＝8.0，1.0Hz，1H)7.14(ddd，J＝8.0，7.5，2.0Hz，1H)7.80(dd，J＝7.5，2.0Hz，1H)
MS?m/e(ESI)522(MH +)
(b) 2-[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base The oxygen base] the benzamide hydrochlorate
With 4-[7-(2-butyne base)-2-(2-carbamyl phenoxyl)-1-methyl-6-oxo-6 of 210mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester mixes with 4N hydrochloric acid-ethyl acetate solution of 3.5ml methanol and 2.1ml.After 4 hours, come concentrated reaction solution in stirring at room at mixture by feeding nitrogen.The residue that generates is washed with ethanol and ethyl acetate, obtains the title compound (96%) of 177mg.
1H-NMR(DMSO-d6)δ1.82(t，J＝2.3Hz，3H)3.28-3.32(m，4H)3.48(s，3H)3.54-3.58(m，4H)5.04(q，2.3Hz，2H)6.96(br.t，J＝7.0Hz，1H)6.99(br.d，J＝8.0Hz，1H)7.46(ddd，J＝8.0，7.0，1.5Hz，1H)7.93(br.d，J＝8.0Hz，1H)
MS?m/e(ESI)422(MH +-HCl)
Embodiment 119
3-(2-butyne base)-5-methyl-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone also
(a) 5-methyl isophthalic acid-trityl-1,5-glyoxalidine be [4,5-d] pyridazine-4-ketone also
At room temperature, 5-methyl isophthalic acid with 78.8g, 5-glyoxalidine also [4,5-d] pyridazine-4-ketone [CAS No.76756-58-6] (Shih-Fong Chen and Raymond P.Panzica, Joumal of OrganicChemistry 46, p2467,1981) be suspended in the 2.5L dichloromethane, and 78.8 triethylamines are added wherein.The 176g trityl chloride is joined in the mixture, then it was stirred 3 hours.The 7.5L ethyl acetate is joined in the mixture.After washing with 3L water and 3L saturated sodium-chloride water solution successively, with mixture through anhydrous magnesium sulfate drying and concentrating under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby from hexane-ethyl acetate (20: 80-0: 100) prepare the title compound of 136.5g the part of eluting.
1H-NMR(CDCl 3)δ3.79(s，3H)6.92(s，1H)7.07-7.13(m，6H)7.32-7.40(m，9H)7.87(s，lH)
(b) 2-chloro-5-methyl isophthalic acid-trityl-1,5-glyoxalidine be [4,5-d] pyridazine-4-ketone also
At-75 ℃ under nitrogen, 220ml hmds lithium (lithium hexa methyl disilazide) (1.0M tetrahydrofuran solution) is joined 5-methyl isophthalic acid-trityl-1 of 68.3g, 5-glyoxalidine also [4,5-d] in the 4-L tetrahydrofuran solution of pyridazine-4-ketone, and mixture stirred 1 hour in-75 ℃.200ml tetrahydrofuran solution with the 82.3g hexachlorethane joins in the solution then.Mixture is warmed to-20 ℃.5% aqueous ammonium chloride solution that adds 5L, and with mixture 4L ethyl acetate extraction.Organic layer is washed with 5L water and 5L saturated sodium-chloride water solution successively.With this solution through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Residue is suspended in the 150ml t-butyl methyl ether, and filters then and collect.Solid washes twice with the 100ml t-butyl methyl ether, obtains the title compound of 69.7g.
1H-NMR(CDCl 3)δ3.78(s，3H)5.81(s，1H)7.25-7.27(m，6H)7.28-7.38(m，9H)
(c) 4-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl) piperazine-1-carboxylic acid uncle Butyl ester
Under nitrogen, with 2-chloro-5-methyl isophthalic acid-trityl-1 of 69.7g, 5-glyoxalidine also [4,5-d] pyridazine-4-ketone mixes with 153.4g piperazine-1-carboxylic acid tertiary butyl ester, and mixture stirred and is heated to 100 ℃.When reactant mixture becomes when being easy to stir, temperature is risen to 150 ℃.Mixture was kept 1 hour under this temperature.The reaction solution cooling also is suspended in the 250ml t-butyl methyl ether then.Filter and collect this float.Solid is washed twice with the 200ml t-butyl methyl ether and washed three times with 200ml.This solid is washed twice and drying with the 200ml t-butyl methyl ether once more, obtained the title compound of 50.3g.
1H-NMR(CDCl 3)δ1.50(s，9H)3.56-3.62(m，4H)3.73-3.80(m，4H)3.87(s，3H)8.16(s，1H)12.65(br.s，lH)
(d) 4-[1-(2-butyne base)-6-methyl-7-oxo-6.7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl] Piperazine-1-carboxylic acid tertiary butyl ester
At 15 ℃ of 4-(6-methyl-7-oxo-6 that under nitrogen, successively the 2-butyne base bromide of 43.9g potassium carbonate and 27.8ml joined 88.4g, 7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl) N of 5.5-L of piperazine-1-carboxylic acid tertiary butyl ester, in the dinethylformamide solution.Reaction solution is at room temperature stirred 22 hours, and be poured into then in the 10L water.Mixture 5L ethyl acetate extraction.Organic layer is also washed twice with the 5L saturated sodium-chloride water solution with 5L water successively.Twice of 3L ethyl acetate extraction of water layer.Organic layer is merged together, and then through anhydrous magnesium sulfate drying.With the organic layer concentrating under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby from hexane-ethyl acetate (3: 2-3: 7) prepare the title compound of 54.3g the part of eluting.
1H-NMR(CDCl 3)δ1.52(s，9H)1.83(t，J＝2.3Hz，3H)3.38-3.42(m，4H)3.61-3.64(m，4H)3.85(s，3H)5.09(q，J＝2.3Hz，2H)8.13(s，1H)
(e) 3-(2-butyne base)-5-methyl-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone also
The 200ml trifluoroacetic acid is joined 4-[1-(2-butyne the base)-6-methyl-7-oxo-6 that contains 54.3g, 7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl] in the 200ml dichloromethane solution of piperazine-1-carboxylic acid tertiary butyl ester, and mixture at room temperature stirred 1 hour.The concentrating under reduced pressure mixture is dissolved in residue in the 500ml ethyl acetate.10% sodium bicarbonate aqueous solution that adds 1L gradually.5N sodium hydrate aqueous solution with 1L ethyl acetate and 500ml joins in this solution then.Separate organic layer.Then with water layer 1L dichloromethane extraction five times.Organic layer is merged together, with the 2N aqueous sodium hydroxide washes of 500ml, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.With the residue re-crystallizing in ethyl acetate, obtain the crystalline title compound of 30.5g.
1H-NMR(CDCl 3)δ1.84(t，J＝2.3Hz，3H)3.05-3.09(m，4H)3.38-3.44(m，4H)3.85(s，3H)5.06(q，J＝2.3Hz，2H)8.13(s，3H)
Embodiment 119-2
3-(2-butyne base)-5-methyl-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone toluene also -4-sulphonic acid ester
With 3-(2-butyne base)-5-methyl-2-(piperazine-1-yl)-3 of 98.7mg, 5-glyoxalidine also [4,5-d] pyridazine-4-ketone is dissolved in the 1ml ethanol, and then this solution is wherein stirred in the 1ml alcoholic solution adding of 101mg p-methyl benzenesulfonic acid monohydrate simultaneously.Mixture was stirred simultaneously with ice-cooled 2 hours.Filter collecting precipitation, and, obtain the title compound of 153.2mg then under reduced pressure in 50 ℃ of dryings 1 hour.
1H-NMR(DMSO-d6)δ1.79(t，J＝2Hz，3H)2.27(s，3H)3.25-3.35(m，4H)3.50-3.54(m，4H)3.70(s，3H)5.13(d，J＝2Hz，2H)7.10(d，J＝8Hz，2H)7.47(d，J＝8Hz，2H)8.25(s，1H)8.79(br.s，2H)
With title compound recrystallization from acetone of 107.95mg, obtain the 84.9mg crystalline product in addition.
Embodiment 120
2-(3-amino piperidine-1-yl)-3-(2-butyne base)-5-methyl-3.5-glyoxalidine is [4.5-d] pyridazine-4-also The ketone trifluoro-acetate
(a) 9H-fluorenes-9-ylmethyl 3-tert-butoxycarbonyl amino piperidine-1-carboxylate
1.84g diisopropylethylamine and 4.71g diphenyl phosphoryl azide are joined in the 10ml t-butanol solution of 9H-fluorenes-9-ylmethyl 3-carboxyl piperidines-1-carboxylate of 5.01g, and with mixture under nitrogen in 60 ℃ of heating 18 hours.Cooled reaction solution, and with the adding of 150ml ethyl acetate wherein.Organic layer is washed with 5% aqueous sulfuric acid of 100ml, 5% sodium bicarbonate aqueous solution, 100ml water and the 100ml saturated sodium-chloride water solution of 100ml successively, and then through anhydrous magnesium sulfate drying.With the organic layer concentrating under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby from the part of hexane-ethyl acetate (4: 1) eluting, prepare the title compound of 1.88g.
1H-NMR(CDCl 3)δ1.45(s，9H)1.45-1.72(m，3H)1.82-1.87(br.s，1H)3.09-3.30(br.s，2H)3.58(br.s，2H)3.82-3.98(br.s，1H)4.24(t，J＝7.2Hz，1H)4.27-4.48(br.s，2H)4.52-4.59(br.s，1H)7.32(dd，J＝10.3，10.0Hz，2H)7.39(t，J＝10.0Hz，2H)7.59(d，J＝10.0Hz，2H)7.75(d，J＝10.3Hz，2H)
(b) piperidines-3-aminocarbamic acid tertiary butyl ester
The 25ml diethylamine is joined in the 250ml alcoholic solution of 9H-fluorenes-9-ylmethyl 3-tert-butoxycarbonyl amino piperidine-1-carboxylate of 1.88g, and with mixture stirring at room 18 hours.After this solution decompression is concentrated, residue is dissolved in the mixture of 10% aqueous citric acid solution that contains 150ml toluene and 100ml.Water layer is alkalized with the 5N sodium hydrate aqueous solution, and use twice of 100ml dichloromethane extraction then.Organic layer is merged together, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure, obtains the title compound of 0.79g.
1H-NMR(CDCl 3)δ1.45(s，9H)1.41-1.53(m，2H)1.65-1.72(m，1H)1.79-1.86(m，1H)2.48-2.56(m，1H)2.64-2.70(m，1H)2.78-2.86(m，1H)3.06(dd，J＝12.0，4.0Hz，1H)3.48-3.62(br.s，1H)4.71-4.88(br.s，1H)
(c) 2-(3-amino piperidine-1-yl)-3-(2-butyne base)-5-methyl-3.5-glyoxalidine [4,5-d] pyridazine also -4-ketone trifluoro-acetate
With 2-chloro-5-methyl isophthalic acid-trityl-1 of 0.020g, 5-glyoxalidine also [4,5-d] pyridazine-4-ketone and 0.040g piperidines-3-aminocarbamic acid tertiary butyl ester mixes, and with mixture under nitrogen in 150 ℃ of heating 1 hour.Reactant mixture is through the silica gel column chromatography purification.Thereby from the part of eluent ethyl acetate, obtain [1-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl) piperidines-3-yl] carbamic acid tertiary butyl ester of 0.016g.This chemical compound of 0.0080g is dissolved in the N of 0.6ml, in the dinethylformamide, and then the 2-butyne base bromide of 0.0038g potassium carbonate and 0.003ml is added wherein.With mixture stirring at room 18 hours.Reactant mixture is distributed between 1ml ethyl acetate and 1ml water, and concentrated organic layer.Residue is dissolved in the 0.5ml dichloromethane, and then the 0.5ml trifluoroacetic acid is added wherein.After 1 hour, concentrated reaction solution.Residue obtains the title compound of 0.0046g through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
1H-NMR(CDCl 3)δ1.74-1.80(br.s，1H)1.82(br.s，3H)1.96-2.19(br.m，3H)3.43-3.79(br.m，5H)3.86(s，3H)5.05(br.d，J＝16.0Hz，1H)5.23(br.d，J＝16.0Hz，1H)8.15(s，1H)
Embodiment 122
2-[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base oxygen base] Benzamide
With 4-[7-(2-butyne base)-2-(2-carbamyl phenoxyl)-1-methyl-6-oxo-6 of 53.0g, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 160ml trifluoroacetic acid, and mixture at room temperature stirred 1 hour.The 2M sodium hydrate aqueous solution of 1250ml is added drop-wise in the reaction solution, and mixture was at room temperature stirred 1 hour 50 minutes again.Filter and collect the white precipitate that generates.Water also whitens the color solid with ethanol, and in 60 ℃ of dried overnight, obtain the title compound of 42.8g then.
1H-NMR(DMSO-d6)δ1.78(t，J＝2.4Hz，3H)2.82-2.86(m，4H)3.18-3.22(m，4H)3.36(s，3H)4.91(q，2.4Hz，2H)6.58(td，J＝8.4，1.2Hz，1H)6.63(dd，J＝8.0，0.8Hz，1H)7.14(ddd，J＝8.0，7.2，2.0Hz，1H)7.80(dd，J＝7.6，2.0Hz，1H)
MS?m/e(ESI)422(MH +)
Embodiment 126
3-[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base sulfane Base] the propanoic acid trifluoro-acetate
4-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6 with 7mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 1-Methyl-2-Pyrrolidone of 0.15ml, and then 3-mercaptopropionic acid and the 6mg potassium carbonate of 20 μ l added wherein.Mixture was at room temperature stirred 5 hours.Saturated ammonium chloride solution is joined in the reaction solution, and use the ethyl acetate extraction mixture.Concentrate organic layer, and residue is dissolved in the 0.40ml trifluoroacetic acid.Concentrate this solution by feeding nitrogen.Residue obtains the title compound of 4.60mg through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
MS?m/e(ESI)391(MH +-CF 3COOH)
Embodiment 129
7-(2-butyne base)-1-methyl-8-(piperazine-1-yl)-2-propylthio alkyl-1,7-dihydro purine-6-one trifluoro Acetas
By same procedure used among the embodiment 126, replace the 3-mercaptopropionic acid by using propane-1-mercaptan, prepare the title compound of 4.61mg.
MS?m/e(ESI)361(MH +-CF 3COOH)
Embodiment 142
7-(2-butyne base)-1-methyl-8-(piperazine-1-yl)-2-(thiazol-2-yl sulfane base)-1,7-dihydro purine-6- The ketone trifluoro-acetate
By same procedure used among the embodiment 126, replace the 3-mercaptopropionic acid by using thiazol-2-thiol, prepare the title compound of 3.86mg.
MS?m/e(ESI)402(MH +-CF 3COOH)
Embodiment 146
7-(2-butyne base)-1-methyl-8-(piperazine-1-yl)-2-[1-(thiophene-2-yl) second sulfane base]-1, the 7-dihydro The purine-6-one trifluoro-acetate
By same procedure used among the embodiment 126, replace the 3-mercaptopropionic acid by using 1-(thiophene-2-yl) ethyl mercaptan, prepare the title compound of 0.51mg.
MS?m/e(ESI)429(MH +-CF 3COOH)
Embodiment 147
7-(2-butyne base)-1-methyl-2-(1-methyl isophthalic acid H-imidazoles-2-base sulfane base)-8-(piperazine-1-yl)-1,7- Dihydro purine-6-one trifluoro-acetate
4-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6 with 5mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 1-Methyl-2-Pyrrolidone of 0.15ml, and then 1-methyl isophthalic acid H-imidazoles-2-mercaptan and the 8mg potassium carbonate of 10mg added wherein.Mixture was at room temperature stirred 5 hours.Saturated ammonium chloride solution is joined in the reaction solution, and use the ethyl acetate extraction mixture.Concentrate organic layer, and residue is dissolved in the 0.40ml trifluoroacetic acid.Concentrate this solution by feeding nitrogen.Residue obtains the title compound of 3.75mg through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
MS?m/e(ESI)399(MH +-CF 3COOH)
Embodiment 159
7-(2-butyne base)-1-methyl-2-(4-methylthiazol-2-base sulfane base)-8-(piperazine-1-yl)-1, the 7-dihydro The purine-6-one trifluoro-acetate
By same procedure used among the embodiment 147, replace 1-methyl isophthalic acid H-imidazoles-2-mercaptan by using 4-methylthiazol-2-mercaptan, prepare the title compound of 4.01mg.
MS?m/e(ESI)416(MH +-CF 3COOH)
Embodiment 229
7-(2-butyne base)-1-(2-cyano group benzyl)-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2- The nitrile hydrochlorate
(a) 4-[7-(2-butyne base)-2-cyano group-1-(2-cyano group benzyl)-6-oxo-6,7-dihydro-1H-purine-8- Base] piperazine-1-carboxylic acid tertiary butyl ester
Contain resulting 4-[7-among the 8mg embodiment 96 (a) (2-butyne base)-2-chloro-1-(2-cyano group benzyl)-6-oxo-6,7-dihydro-1H-purine-8-yl] N of piperazine-1-carboxylic acid tertiary butyl ester, 10mg Cyanogran. and 0.3ml, the mixture of dinethylformamide at room temperature stirred 4 hours.Reactant mixture is with the extraction of ethyl acetate-water, and with the organic layer water, and wash with saturated salt then.Concentrate organic layer.Residue obtains the title compound of 6.1mg through thin layer chromatography (50% ethyl acetate/hexane) purification.
1H-NMR(CDCl 3)δ1.50(s，9H)1.83(s，3H)3.50(s，4H)3.58-3.64(m，4H)4.99(s，2H)5.74(s，2H)7.02(d，J＝8Hz，1H)7.44(t，J＝8Hz，1H)7.55(t，J＝8Hz，1H)7.74(d，J＝8Hz，1H)
(b) 7-(2-butyne base)-1-(2-cyano group benzyl)-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine -2-nitrile hydrochlorate
4-[7-(2-butyne base)-2-cyano group-1-(2-cyano group the benzyl)-6-oxo-6 that will contain 6.1mg, 7-dihydro-1H-purine-8-yl] mixture of piperazine-1-carboxylic acid tertiary butyl ester and 0.2ml trifluoroacetic acid at room temperature stirred 20 minutes.Concentrated reaction solution, and, obtain the title compound of 5.0mg with the reversed-phase column chromatography method purification of residue through use 20%-60% methanol (0.1% concentrated hydrochloric acid) solvent.
1H-NMR(DMSO-d6)δ1.80(s，3H)3.30(s，4H)3.60-3.70(m，4H)5.09(s，2H)5.60(s，2H)7.27(d，J＝8Hz，1H)7.54(t，J＝8Hz，1H)7.68(t，J＝8Hz，1H)7.94(d，J＝8Hz，1H)9.36(br.s，2H)
Embodiment 230
3-[7-(2-butyne base)-1-(2-cyano group benzyl)-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine -2-base oxygen base] pyridine-2-carboxylic acid amides trifluoro-acetate
4-[7-(2-butyne base)-2-chloro-1-(2-cyano group benzyl)-6-oxo-6 with 7mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 1-Methyl-2-Pyrrolidone of 0.2ml, and then 3-pyridone-2-carboxylic acid amides and the 8mg potassium carbonate of 8mg added wherein.Mixture was stirred 2 hours in 100 ℃.1N hydrochloric acid is joined in the reactant mixture, and use the ethyl acetate extraction mixture.Concentrate organic layer, and residue is dissolved in the trifluoroacetic acid.Concentrate this solution, and with residue through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification, obtain the title compound of 2.93mg.
MS?m/e(ESI)524(MH +-CF 3COOH)
Embodiment 234
2-[7-(2-butyne base)-1-(2-cyano group benzyl)-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine -2-base oxygen base] the benzamide trifluoro-acetate
According to the method described in the embodiment 230, replace 3-pyridone-2-carboxylic acid amides by using salicylamide, prepare the title compound of 3.74mg.
MS?m/e(ESI)523(MH +-CF 3COOH)
Embodiment 235
2-[7-(2-butyne base)-1-(4-cyano group benzyl)-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine -2-base oxygen base] the benzamide trifluoro-acetate
(a) 4-[7-(2-butyne base)-2-chloro-1-(4-cyano group benzyl)-6-oxo-6,7-dioxy-1H-purine-8-yl] Piperazine-1-carboxylic acid tertiary butyl ester
With 4-[7-(2-butyne base)-2-chloro-6-oxo-6 of 100mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the N of 1.2ml, in the dinethylformamide, and then 4-cyano-benzyl bromide and the 68mg potassium carbonate of 97mg added wherein.Mixture at room temperature stirred 4 hours.Saturated aqueous ammonium chloride is joined in the reactant mixture, and use the ethyl acetate extraction mixture.Concentrate organic layer, and with residue through the silica gel chromatography purification, obtain the title compound of 71mg.
1H-NMR(CDCl3)δ1.49(s，9H)1.84(t，J＝2.5Hz，3H)3.43-3.47(m，4H)3.59-3.63(m，4H)4.94(q，2.5Hz，2H)5.53(s，2H)7.42(d，J＝8.0Hz，2H)7.62(d，J＝8.0Hz，2H)
(b) (piperazine-1-yl)-6.7-dihydro-1H-is fast for 2-[7-(2-butyne base)-1-(4-cyano group benzyl)-6-oxo-8- Purine-2-base oxygen base] the benzamide trifluoro-acetate
4-[7-(2-butyne base)-2-chloro-1-(4-cyano group benzyl)-6-oxo-6 with 12mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 1-Methyl-2-Pyrrolidone of 0.3ml, and then 10mg salicylamide and 10mg potassium carbonate are added wherein.Mixture was stirred 12 hours in 100 ℃.1N hydrochloric acid is joined in the reaction solution, and use the ethyl acetate extraction mixture.Concentrate organic layer, and residue is dissolved in the trifluoroacetic acid.Concentrate this solution, and with residue through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification, obtain the title compound of 6.69mg.
MS?m/e(ESI)523(MH +-CF 3COOH)
Embodiment 238
2-[7-(2-butyne base)-1-(3-cyano group benzyl)-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine -2-base oxygen base] the benzamide trifluoro-acetate
(a) 4-[7-(2-butyne base)-2-chloro-1-(3-cyano group benzyl)-6-oxo-6,7-dihydro-1H-purine-8-yl] Piperazine-1-carboxylic acid tertiary butyl ester
With 4-[7-(2-butyne base)-2-chloro-6-oxo-6 of 100mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the N of 1.2ml, in the dinethylformamide, and then 3-cyano-benzyl bromide and the 68mg potassium carbonate of 97mg added wherein.Mixture at room temperature stirred 12 hours.Then saturated ammonium chloride solution is joined in the reaction solution, and use the ethyl acetate extraction mixture.Concentrate organic layer, and with residue through the silica gel chromatography purification, obtain the title compound of 71mg.
1H-NMR(CDCl3)δ1.49(s，9H)1.84(t，J＝2.5Hz，3H)3.43-3.47(m，4H)3.59-3.63(m，4H)4.94(q，2.5Hz，2H)5.53(s，2H)7.42(d，J＝8.0Hz，2H)7.62(d，J＝8.0Hz，2H)
(b) (piperazine-1-yl)-6.7-dihydro-1H-is fast for 2-[7-(2-butyne base)-1-(3-cyano group benzyl)-6-oxo-8- Purine-2-base oxygen base] the benzamide trifluoro-acetate
4-[7-(2-butyne base)-2-chloro-1-(3-cyano group benzyl)-6-oxo-6 with 12mg, 7-dihydro-1H-purine-8-yl] piperazine-1-carboxylic acid tertiary butyl ester is dissolved in the 1-Methyl-2-Pyrrolidone of 0.3ml, and then 10mg salicylamide and 10mg potassium carbonate are added wherein.Mixture was stirred 5 hours in 100 ℃.1N hydrochloric acid is joined in the reaction solution, and use the ethyl acetate extraction mixture.Concentrate organic layer, and residue is dissolved in the trifluoroacetic acid.Concentrate this solution, and with residue through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification, obtain the title compound of 8.76mg.
MS?m/e(ESI)523(MH +-CF 3COOH)
Embodiment 242
8-(3-amino piperidine-1-yl)-7-(2-butyne base)-1-(2-cyano group benzyl)-6-oxo-6,7-dihydro-1H-is fast Purine-2-nitrile hydrochlorate
(a) 3-tert-butoxycarbonyl amino piperidine-1-carboxylic acid benzyl ester
With 30 minutes time, 88g benzyl chloroformate (30% toluene solution) is added drop-wise in the mixture that contains 24.3g piperidines-3-carboxylic acid, ethyl ester, 26ml triethylamine and 300ml ethyl acetate, simultaneously with mixture with ice-cooled.Filter reaction mixture is to remove insoluble matter.With filtrate again by a small amount of filtered through silica gel.Concentrated filtrate.
The 5M sodium hydrate aqueous solution of 200ml ethanol and 40ml is joined in the residue.Mixture at room temperature stirred spend the night.Concentrated reaction solution, and 200ml water joined in the residue.Mixture is extracted with t-butyl methyl ether.The 5M aqueous hydrochloric acid solution is joined in the water layer, and use the ethyl acetate extraction mixture.With the organic layer water, and wash with saturated salt then.Organic layer through anhydrous magnesium sulfate drying, and is concentrated then, obtain buttery residue (30.9g).
The mixture that will contain this residue of 30g, 24.5ml diphenyl phosphoryl azide, 15.9ml triethylamine and the 250ml tert-butyl alcohol at room temperature stirred 1.5 hours.Mixture was further stirred 20 hours in 100 ℃ in oil bath.Concentrated reaction solution, and with residue ethyl acetate-water extraction.With organic layer with dilute aqueous solution of sodium bicarbonate, and wash with saturated salt then.Organic layer through anhydrous magnesium sulfate drying, and is concentrated then.Residue through using the silica gel column chromatography purification of 10%-20% ethyl acetate/hexane, subsequently by ethyl acetate-hexane recrystallization, is obtained the title compound of 21.4g.
1H-NMR(CDCl 3)δ1.43(s，9H)1.48-1.92(m，4H)3.20-3.80(m，5H)4.58(br.s，1H)5.13(s，2H)7.26-7.40(m，5H)
(b) piperidines-3-aminocarbamic acid tertiary butyl ester
Under hydrogen, will contain the 10% palladium carbon of 3-tert-butoxycarbonyl amino piperidine-1-benzyl carboxylate, 500mg of 10g and the alcoholic acid mixture of 100ml and at room temperature stir and spend the night.By removing by filter catalyst.Concentrated filtrate is also dry, obtains the title compound of 6.0g.
1H-NMR(CDCl 3)δ1.44(s，9H)1.47-1.80(m，4H)2.45-2.60(m，1H)2.60-2.75(m，1H)2.75-2.90(m，1H)3.05(dd，J＝3Hz，12Hz，1H)3.57(br.s，1H)4.83(br.s，1H)
(c) [1-[7-(2-butyne base)-2,6-two chloro-7H-purine-8-yls] piperidines-3-yl] the carbamic acid tert-butyl group Ester
The 7-(2-butyne base)-2,6 that will contain 1.25g, the mixture of 8-three chloro-7H-purine, 1.0g piperidines-3-aminocarbamic acid tertiary butyl ester and 10ml acetonitrile at room temperature stirred 10 minutes.Drip the 0.63ml triethylamine with times of 10 minutes, and then with mixture in room temperature continuous stirring 30 minutes.Reaction solution is distributed between ethyl acetate and water, and organic layer is washed with saturated salt.Organic layer through anhydrous magnesium sulfate drying, and is concentrated then.Residue obtains the title compound of 1.79g with t-butyl methyl ether-hexane crystallization.
1H-NMR(CDCl 3)δ1.43(s，9H)1.60-2.02(m，4H)1.83(t，J＝2Hz，3H)3.32-3.41(m，1H)3.42-3.52(m，1H)3.67-3.76(m，1H)3.80-3.91(m，1H)4.76-4.90(m，3H)
(d) [1-[7-(2-butyne base)-2-chloro-6-oxo-6,7-dihydro-1H-purine-8-yl] piperidines-3-yl] amino The formic acid tertiary butyl ester
[1-[7-(2-butyne base)-2, the 6-two chloro-7H-purine-8-yls] piperidines-3-yl that will contain 1.79g] mixture of carbamic acid tertiary butyl ester, 1.0g sodium acetate and 18ml dimethyl sulfoxine stirred 3 hours in 120 ℃ in oil bath.Mixture is taken out from oil bath, and 18ml water is joined in the reaction solution.Mixture is cooled to room temperature.Filter to collect crystallization, and water, wash with t-butyl methyl ether then.Dried crystals then obtains the title compound of 1.59g.
1H-NMR(DMSO-d6)δ1.39(s，9H)1.34-1.88(m，4H)1.78(s，3H)2.81(t，J＝11Hz，1H)2.95(t，J＝11Hz，1H)3.48-3.60(m，2H)3.64(d，J＝6Hz，1H)4.90(s，2H)6.94(d，J＝8Hz，1H)
(e) [1-[7-(2-butyne base)-2-chloro-1-(2-cyano group benzyl)-6-oxo-6,7-dihydro-1H-purine-8-yl] Piperidines-3-yl] the carbamic acid tertiary butyl ester
[the 1-[7-(2-butyne base)-2-chloro-6-oxo-6 that will contain 100mg, 7-dihydro-1H-purine-8-yl] piperidines-3-yl] carbamic acid tertiary butyl ester, 66mg Anhydrous potassium carbonate, the 2-cyano-benzyl bromide of 70mg and the N of 1ml, the mixture of dinethylformamide at room temperature stirred 5 hours.Reaction solution is distributed between ethyl acetate and water, and with the organic layer water, and wash with saturated salt then.Organic layer through anhydrous magnesium sulfate drying, and is concentrated then.Residue obtains the title compound of 44.7mg through using the silica gel column chromatography purification of 50% ethyl acetate/hexane.
1H-NMR(CDCl 3)δ1.44(s，9H)1.59-1.81(m，2H)1.83(t，J＝2Hz，3H)1.86-1.94(m，2H)3.20-3.50(m，3H)3.66(d，J＝7Hz，1H)3.86(br.s，1H)4.88-5.06(m，3H)5.72(s，2H)7.06(d，J＝8Hz，1H)7.38(t，J＝8Hz，1H)7.51(t，J＝8Hz，1H)7.70(d，J＝8Hz，1H)
(f) [1-[7-(2-butyne base)-2-cyano group-1-(2-cyano group benzyl)-6-oxo-6.7-dihydro-1H-purine-8- Base] piperidines-3-yl] the carbamic acid tertiary butyl ester
[the 1-[7-(2-butyne base)-2-chloro-1-(2-cyano group benzyl)-6-oxo-6 that will contain 15mg, 7-dihydro-1H-purine-8-yl] piperidines-3-yl] N of carbamic acid tertiary butyl ester, 20mg Cyanogran. and 0.2ml, the mixture of dinethylformamide at room temperature stirred 3 hours.Reaction solution is distributed between ethyl acetate and water, and with the organic layer water, and wash with saturated salt then.Concentrate organic layer then, and, obtain the title compound of 10.3mg the thin layer chromatography purification (showing layer three times) of residue through using 50% ethyl acetate/hexane solvent.
1H-NMR(CDCl 3)δ1.44(s，9H)1.52-1.98(m，4H)1.81(t，J＝2Hz?3H)3.24(dd，J＝7Hz，12Hz，1H)3.30-3.40(m，1H)3.46-3.56(m，1H)，3.72(d，J＝12Hz，1H)3.86(br.s，1H)4.86-5.10(m，3H)5.73(s，2H)7.00(d，J＝8Hz，1H)7.42(t，J＝8Hz，1H)7.54(dt，J＝2Hz，8Hz，1H)7.73(dd，J＝2Hz，8Hz，1H)
(g) 8-(3-amino piperidine-1-yl)-7-(2-butyne base)-1-(2-cyano group benzyl)-6-oxo-6, the 7-dihydro -1H-purine-2-nitrile hydrochlorate
[1-[7-(2-butyne base)-2-cyano group-1-(2-cyano group benzyl)-6-oxo-6, the 7-dihydro-1H-purine-8-yl] piperidines-3-yl that will contain 10.3mg] mixture of carbamic acid tertiary butyl ester and 0.2ml trifluoroacetic acid stirred 20 minutes.Concentrated reaction solution, and, obtain the title compound of 8.0mg with the reversed-phase column chromatography method purification of residue through use 20%-80% methanol (0.1% concentrated hydrochloric acid) solvent.
1H-NMR(DMSO-d6)δ1.60-1.74(m，2H)1.79(t，J＝2Hz，3H)1.88-2.03(m，2H)3.14-3.28(m，2H)3.42(br.s，1H)3.52-3.82(m，2H)4.98-5.12(m，2H)5.58(s，2H)7.26(d，J＝8Hz，1H)7.53(t，J＝8Hz，1H)7.66(t，J＝8Hz，1H)7.93(d，J＝8Hz，1H)8.16(br.s，3H)
Embodiment 243
2-[8-(3-amino piperidine-1-yl)-7-(2-butyne base)-2-methoxyl group-6-oxo-6,7-dihydro purine-1-base Methyl] the benzonitrile hydrochlorate
[1-[7-(2-butyne base)-2-chloro-1-(2-cyano group benzyl)-6-oxo-6, the 7-dihydro-1H-purine-8-yl] piperidines-3-yl that will contain 15mg] carbamic acid tertiary butyl ester, 20mg Anhydrous potassium carbonate and 0.2ml methanol mixture stirred 3 hours.Used same steps as is carried out follow-up step according to embodiment 242 (f) and (g).Thereby synthesising title compound.
1H-NMR(DMSO-d6)δ1.58-1.72(m，2H)1.84-1.94(m，1H)1.96-2.04(m，1H)3.08-3.20(m，2H)3.36-3.70(m，3H)3.90(s，3H)4.90-5.02(m，2H)5.32(s，2H)7.20(d，J＝8Hz，1H)7.47(t，J＝8Hz，1H)7.63(t，J＝8Hz，1H)7.87(d，J＝8Hz，1H)8.12(br.s，3H)
Embodiment 248
2-[8-(3-amino piperidine-1-yl)-7-(2-butyne base)-1-methyl-6-oxo-6,7-dihydro-1H-purine-2- Base oxygen base] the benzamide trifluoroacetate
(a) [1-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purine-8-yl] piperidines-3- Base] the carbamic acid tertiary butyl ester
[1-[7-(2-butyne base)-2-chloro-6-oxo-6,7-dihydro-1H-purine-8-yl] piperidines-3-yl with 700mg] the carbamic acid tertiary butyl ester is dissolved in the 7.0ml dimethyl sulfoxine, and then 114 μ l iodomethane and 299mg potassium carbonate are added wherein.Mixture at room temperature stirred 30 minutes, and 40ml water is joined in the reaction solution.Mixture at room temperature stirred 30 minutes, and filtered and collect white precipitate.The white solid water that generates, and wash with hexane then, obtain the title compound of 540mg.
1H-NMR(CDCl3)δ1.44(s，9H)1.72-1.94(m，4H)1.81(t，J＝2.4Hz，3H)3.16-3.92(m，5H)3.72(s，3H)4.91(dd，J＝17.6，2.4Hz，1H)5.01(d，J＝17.6Hz，1H)
(b) 2-[8-(3-amino piperidine-1-yl)-7-(2-butyne base)-1-methyl-6-oxo-6,7-dihydro-1H-is fast Purine-2-base oxygen base] the benzamide trifluoro-acetate
[1-[7-(2-butyne base)-2-chloro-1-methyl-6-oxo-6 with 10mg, 7-dihydro-1H-purine-8-yl] piperidines-3-yl] the carbamic acid tertiary butyl ester is dissolved in the 1-Methyl-2-Pyrrolidone of 0.3ml, and then 10mg salicylamide and 10mg potassium carbonate are added wherein.Mixture was stirred 2 hours in 100 ℃.1N hydrochloric acid is joined in the reaction solution, and use the ethyl acetate extraction mixture.Concentrate organic layer, and residue is dissolved in the trifluoroacetic acid.Concentrate this solution, and with residue through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification, obtain the title compound of 5.54mg.
MS?m/e(ESI)436(MH +-CF 3COOH)
Embodiment 258
3-(2-butyne base)-2-(piperazine-1-yl)-5-(2-propynyl)-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-also The ketone trifluoro-acetate
(a) 4-[1-(2-butyne base)-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl] piperazine-1- The carboxylic acid tertiary butyl ester
At room temperature, 3-(2-butyne base)-2-(piperazine-1-yl)-3 that 4-dimethylaminopyridine and the 0.645g Bis(tert-butoxycarbonyl)oxide of 0.299g triethylamine, 0.023g joined 0.448g, 5-glyoxalidine also [4,5-d] N of 20ml of pyridazine-4-ketone trifluoro-acetate, in the dinethylformamide solution, and with mixture stirring 5 hours.5N sodium hydrate aqueous solution with 2ml joins in this solution then, and mixture was stirred 1 hour.Reaction solution is poured in the mixture of 200ml ethyl acetate and 100ml saturated aqueous ammonium chloride.Organic layer is also washed twice with the 100ml saturated sodium-chloride water solution then with 100ml water.Organic liquid is through dried over mgso, and concentrating under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby from the part of eluent ethyl acetate, prepare the title compound of 0.298g.
1H-NMR(CDCl 3)δ1.50(s，9H)1.84(t，J＝2.3Hz，3H)3.41(m，4H)3.63(m，4H)5.06(q，J＝2.3Hz，2H)8.17(s，1H)9.92(br.s，1H)
(b) 3-(2-butyne base)-2-(piperazine-1-yl)-5-(2-propynyl)-3, the 5-glyoxalidine is [4,5-d] pyridazine also -4-ketone trifluoro-acetate
The 3-bromo-1-propine of 0.005g potassium carbonate and 0.003ml is joined 4-[1-(2-butyne base)-7-oxo-6 of the 0.010g of 0.5ml, 7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl] N of piperazine-1-carboxylic acid tertiary butyl ester, in the dinethylformamide solution, and mixture at room temperature stirred 10 hours.1ml ethyl acetate and 1ml water are joined in the reaction solution, and layering.Concentrate organic layer, and the residue that generates is dissolved in the mixture that contains 0.5ml dichloromethane and 0.5ml trifluoroacetic acid.Mixture was stirred 1 hour, and concentrate then.Residue obtains the title compound of 0.011g through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
MS?m/e(ESI)311.29(MH +-CF 3COOH)
Embodiment 266
3-(2-butyne base)-5-[2-(3-methoxyphenyl)-2-oxoethyl]-2-(piperazine-1-yl)-3,5-dihydro miaow Azoles is [4,5-d] pyridazine-4-ketone trifluoro-acetate also
According to the method described in the embodiment 258 (b), by using 4-[1-(2-butyne base)-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl] piperazine-1-carboxylic acid tertiary butyl ester and 2-bromo-3 '-methoxyacetophenone, prepare title compound.
MS?m/e(ESI)421.33(MH +-CF 3COOH)
Embodiment 267
2-[3-(2-butyne base)-4-oxo-2-(piperazine-1-yl)-3,4-glyoxalidine also (4,5-d] pyridazine-5-Ji Jia Base] the benzonitrile trifluoro-acetate
According to the method described in the embodiment 258 (b), by using 4-[1-(2-butyne base)-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl] piperazine-1-carboxylic acid tertiary butyl ester and 2-bromomethyl benzonitrile, prepare title compound.
1H-NMR(CD 3OD)δ1.81(t，J＝2.5Hz，3H)3.45-3.49(m，4H)3.66-3.70(m，4H)5.15(q，J＝2.5Hz，2H)5.62(s，2H)7.34(dd，J＝7.6，1.5Hz，1H)7.45(td，J＝7.6，1.5Hz，1H)7.59(td，J＝7.6，1.7Hz，1H)7.75(dd，J＝7.6，1.7Hz，1H)8.25(s，1H)
MS?m/e(ESI)388.32(MH +-CF 3COOH)
Embodiment 297
2-[3-(2-butyne base)-4-oxo-2-(piperazine-1-yl)-3, the 4-glyoxalidine is [4,5-d] pyridazine-5-Ji Jia also Base]-3-fluorine benzonitrile trifluoro-acetate
According to the method described in the embodiment 258 (b), by using 4-[1-(2-butyne base)-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl] piperazine-1-carboxylic acid tertiary butyl ester and 2-bromomethyl-3-fluorine benzonitrile, prepare title compound.
MS?m/e(ESI)406.25(MH +-CF 3COOH)
Embodiment 308
3-benzyl-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone trifluoro-acetate also
(a) 4-(1-benzyl-6-benzyloxy methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2- Base) piperazine-1-carboxylic acid tertiary butyl ester
According to the method described in the embodiment 116 (d),, prepare title compound by using 4-(6-benzyloxy methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl) piperazine-1-carboxylic acid tertiary butyl ester and benzyl bromide a-bromotoluene.
1H-NMR(CDCl 3)δ1.48(s，9H)3.13-3.18(m，4H)3.50-3.54(m，4H)4.72(s，2H)5.61(s，2H)5.65(s，2H)7.20-7.35(m，10H)8.22(s，1H)
(b) 3-benzyl-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone trifluoro-acetate also
According to the method described in the embodiment 117,, obtain title compound by handling 4-(1-benzyl-6-benzyloxy methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl) piperazine-1-carboxylic acid tertiary butyl ester.
1H-NMR(CD 3OD)δ3.31-3.37(m，4H)3.40-3.46(m，4H)5.68(s，2H)7.22-7.36(m，5H)8.25(s，1H)
MS?m/e(ESI)311.24(MH +-CF 3COOH)
Embodiment 309
3-benzyl-5-methyl-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone trifluoroacetic acid also Ester
(a) 4-(1-benzyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl) piperazine-1-carboxylic acid uncle Butyl ester
According to the method described in the embodiment 258 (a), by using 3-benzyl-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone trifluoro-acetate also, prepares title compound.
1H-NMR(CDCl 3)δ1.47(s，9H)3.12-3.16(m，4H)3.47-3.52(m，4H)5.58(s，2H)7.20-7.34(m，5H)8.20(s，1H)10.04(br.s，1H)
(b) 3-benzyl-5-methyl-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone trifluoro second also Acid esters
According to the method described in the embodiment 258 (b),, prepare title compound by using 4-(1-benzyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl) piperazine-1-carboxylic acid tertiary butyl ester and iodomethane.
1H-NMR(CD 3OD)δ3.29-3.35(m，4H)3.36-3.41(m，4H)3.83(s，3H)5.68(s，2H)7.21-7.34(m，5H)8.20(s，1H)
MS?m/e(ESI)325.01(MH +-CF 3COOH)
Embodiment 311
3-benzyl-5-(2-phenylethyl)-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone three also Ethyl fluoroacetate
According to the method described in the embodiment 258 (b), by using 4-[1-benzyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine-2-yl] piperazine-1-carboxylic acid tertiary butyl ester and (2-bromoethyl) benzene, prepare title compound.
1H-NMR(CDCl 3)δ3.11(t，J＝8.1Hz，2H)3.24-3.29(m，4H)3.37-3.42(m，4H)4.46(t，J＝8.1Hz，2H)5.58(s，2H)7.09-7.34(m，10H)8.20(s，1H)
MS?m/e(ESI)415.54(MH +-CF 3COOH)
Embodiment 332
1-(2-butyne base)-6-methyl-7-oxo-2-(piperazine-1-yl)-6, the 7-glyoxalidine is [4,5-d] pyridazine-4-also The Methanamide trifluoro-acetate
(a) 4-[1-(2-butyne base)-4-(cyano group-hydroxymethyl)-5-methoxycarbonyl-1H-imidazoles-2-yl] piperazine -1-carboxylic acid tertiary butyl ester
0.200g Cyanogran. and 0.010ml acetic acid are joined 4-[1-(2-butyne base)-5-methoxycarbonyl-4-formoxyl-1H-imidazoles-2-yl of 15ml] in the acetonitrile solution of piperazine-1-carboxylic acid tertiary butyl ester, and mixture at room temperature stirred 16 hours.The 100ml ethyl acetate is joined in the solution, and with mixture with 50ml water, and wash twice with the 50ml saturated sodium-chloride water solution then.Organic layer is through dried over mgso, and the concentrating under reduced pressure solvent.Residue is through the silica gel column chromatography purification.Thereby from the part of ethyl acetate-hexane (2: 3) eluting, prepare the title compound of 0.274g.
1H-NMR(CDCl 3)δ1.49(s，9H)1.83(t，J＝2.5Hz，3H)3.19-3.23(m，4H)3.56-3.60(m，4H)3.95(s，3H)4.68(d，J＝9.0Hz，1H)4.82(q，J＝2.5Hz，2H)5.72(d，J＝9.0Hz，1H)
(b) 4-[1-(2-butyne base)-4-(carbamoyl-hydroxymethyl)-5-methoxycarbonyl-1H-imidazoles-2- Base] piperazine-1-carboxylic acid tertiary butyl ester
In 5 ℃, 28% ammonia spirit of 30% aqueous hydrogen peroxide solution of 3.2ml and 3.2ml is joined 4-[1-(2-butyne base)-4-(cyano group-hydroxymethyl)-5-methoxycarbonyl-1H-imidazoles-2-yl of the 0.274g of 8ml] in the methanol solution of piperazine-1-carboxylic acid tertiary butyl ester, and mixture stirred 15 hours.The saturated sodium sulfite solution of 100ml is joined in this solution, and with twice of 100ml ethyl acetate extraction of mixture.Organic layer is merged together.With the organic layer that merges through dried over mgso, and concentrating under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby from the part of methanol-ethyl acetate (1: 9) eluting, prepare the title compound of 0.039g.
1H-NMR(CDCl 3)δ1.48(s，9H)1.83(t，J＝2.5Hz，3H)3.13-3.25(m，4H)3.54-3.57(m，4H)3.91(s，3H)4.33-4.37(br.s，1H)4.77(q，J＝2.5Hz，2H)5.54(s，1H)5.63(s，1H)6.82(s，1H)
(c) 4-[4-amidoxalyl base-1-(2-butyne base)-5-methoxycarbonyl-1H-imidazoles-2-yl] piperazine-1-carboxylic The acid tertiary butyl ester
Under 0 ℃; the dimethyl sulfoxide solution of the 0.058g sulfur trioxide pyridine of 0.051ml triethylamine and 1ml is joined 4-[1-(2-butyne base)-4-(carbamoyl-hydroxymethyl)-5-methoxycarbonyl-1H-imidazoles-2-yl of the 0.038g of 2ml] in the dichloromethane solution of piperazine-1-carboxylic acid tertiary butyl ester, and mixture at room temperature stirred 15 hours.The dimethyl sulfoxide solution that adds the 0.116g sulfur trioxide pyridine of 0.102ml triethylamine and 1ml then, and mixture at room temperature stirred 8 hours.The 50ml ethyl acetate is joined in the solution, and organic layer is washed with 1% aqueous sulfuric acid, 20ml saturated sodium bicarbonate aqueous solution and the 20ml saturated sodium-chloride water solution of 20ml successively.Organic layer is through dried over mgso, and concentrating under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby from the part of ethyl acetate-hexane (2: 1) eluting, prepare the title compound of 0.021g.
1H-NMR(CDCl 3)δ1.48(s，9H)1.82(t，J＝2.5Hz，3H)3.19-3.23(m，4H)3.56-3.59(m，4H)3.84(s，3H)4.84(q，J＝2.5Hz，2H)5.62(br.s，1H)7.02(br.s，1H)
(d) 4-[1-(2-butyne base)-4-carbamoyl-6-methyl-7-oxo-6,7-dihydro-1H-glyoxalidine And [4,5-d] pyridazine-2-yl] piperazine-1-carboxylic acid tertiary butyl ester
According to the method described in the embodiment 115 (h), by using 4-[4-amidoxalyl base-1-(2-butyne base)-5-methoxycarbonyl-1H-imidazoles-2-yl] piperazine-1-carboxylic acid tertiary butyl ester, prepare title compound.
1H-NMR(CDCl 3)δ1.50(s，9H)1.84(t，J＝2.3Hz，3H)3.46-3.50(m，4H)3.63-3.66(m，4H)3.99(s，3H)5.12(q，J＝2.3Hz，2H)6.16(s，1H)8.85(s，1H)
(e) 1-(2-butyne base)-6-methyl-7-oxo-2-(piperazine-1-yl)-6, the 7-glyoxalidine is [4,5-d] pyridazine also -4-Methanamide trifluoro-acetate
According to the method described in the embodiment 115 (i); by using 4-[1-(2-butyne base)-4-carbamoyl-6-methyl-7-oxo-6; 7-dihydro-1H-glyoxalidine is [4,5-d] pyridazine-2-yl also] piperazine-1-carboxylic acid tertiary butyl ester, prepare title compound.
MS?m/e(ESI)330.18(MH +-CF 3COOH)
Embodiment 338
3-(2-butyne base)-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-c] pyridine-4-ketone trifluoro-acetate also (a) 2-bromo-1-(2-butyne base)-1H-imidazoles-45-dintrile
50ml N with 69.8g potassium carbonate and 74ml 1-bromo-2-butyne, dinethylformamide solution joins the 2-bromo-1H-imidazoles-4 of the 90.6g of 520ml, the N of 5-dintrile [CAS No 50847-09-1], in the dinethylformamide solution, and with mixture in 50 ℃ the heating 8 hours.1L ethyl acetate and 500ml water are joined in the solution, and with organic layer with 500ml water, and wash twice with the 500ml saturated sodium-chloride water solution then.Organic layer is through dried over mgso, and concentrating under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby from the part of ethyl acetate-hexane (1: 4) eluting, prepare the title compound of 48.0g.
1H-NMR(CDCl 3)δ1.87(t，J＝2.3Hz，3H)4.85(q，J＝2.3Hz，2H)
(b) 2-bromo-1-(2-butyne base)-5-cyano group-1H-imidazoles-4-carboxylic acid, ethyl ester
The 25ml concentrated sulphuric acid is joined 2-bromo-1-(2-butyne base)-1H-imidazoles-4 of the 48.0g of 500ml, in the alcoholic solution of 5-dintrile, and with mixture heated backflow 110 hours.Reaction solution is cooled to room temperature, and concentrating under reduced pressure then.Residue is dissolved in the mixture that contains 500ml ethyl acetate and 500ml water, and uses potassium hydroxide that the pH of solution is transferred to 8.With water layer 500ml ethyl acetate extraction, and organic layer is merged together.Organic layer is through dried over mgso, and concentrating under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby from the part of ethyl acetate-hexane (1: 3) eluting, prepare the title compound of 21.7g.
1H-NMR(CDCl 3)δ1.43(t，J＝7.0Hz，3H)1.87(t，J＝2.3Hz，3H)4.46(q，J＝7.0Hz，2H)4.85(q，J＝2.3Hz，2H)
(c) 4-[1-(2-butyne base)-5-cyano group-4-ethoxy carbonyl-1H-imidazoles-2-yl] piperazine-1-carboxylic acid uncle fourth The base ester
According to the method described in the embodiment 115 (b),, prepare the title compound of 25.1g by using 2-bromo-1-(2-butyne base)-5-cyano group-1H-imidazoles-4-carboxylic acid, ethyl ester of 21.7g.
1H-NMR(CDCl 3)δ1.43(t，J＝7.0Hz，3H)1.49(s，9H)1.87(t，J＝2.3Hz，3H)3.22-3.26(m，4H)3.56-3.61(m，4H)4.44(q，J＝7.0Hz，2H)4.68(q，J＝2.3Hz，2H)
(d) 4-[1-(2-butyne base)-4-carboxyl-5-cyano group-1H-imidazoles-2-yl] piperazine-1-carboxylic acid tertiary butyl ester
The 5N sodium hydrate aqueous solution of 16ml is joined 4-[1-(2-butyne base)-5-cyano group-4-ethoxy carbonyl-1H-imidazoles-2-yl of the 25.1g of 500ml] in the alcoholic solution of piperazine-1-carboxylic acid tertiary butyl ester, and mixture at room temperature stirred two hours.Concentrating under reduced pressure solvent then.Residue is dissolved in the mixture that contains 1L ethyl acetate and 500ml water.The 2N hydrochloric acid of 50ml is joined in the solution.Organic layer is washed with the 200ml saturated sodium-chloride water solution, and through dried over mgso.The concentrating under reduced pressure organic liquid obtains the title compound of 23.2g.
1H-NMR(CDCl 3)δ1.49(s，9H)1.87(t，J＝2.3Hz，3H)3.22-3.26(m，4H)3.56-3.61(m，4H)4.68(q，J＝2.3Hz，2H)
(e) 4-[1-(2-butyne base)-5-cyano group-4-hydroxymethyl-1H-imidazoles-2-yl] piperazine-1-carboxylic acid tert-butyl group Ester
Under-10 ℃, with the 6.9g triethylamine and then the tetrahydrofuran solution of the 10.19g isobutyl chlorocarbonate of 100ml is added drop-wise to the 4-[1-that contains 22.9g (2-butyne base)-4-carboxyl-5-cyano group-1H-imidazoles-2-yl of 600ml] in the oxolane of piperazine-1-carboxylic acid tertiary butyl ester.Remove by filter post precipitation, solution is cooled to once more-10 ℃.The aqueous solution of the 9.45g sodium borohydride of 100ml is added drop-wise in this solution.After 1 hour, 500ml ethyl acetate and 500ml water are joined in this solution.Use 1N hydrochloric acid that the pH value of solution is transferred to 5, and use saturated sodium bicarbonate aqueous solution that pH value is transferred to 10 then.Organic layer is washed with 500ml water and 500ml saturated sodium-chloride water solution successively.Organic layer is through dried over mgso, and concentrating under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby from the part of ethyl acetate-hexane (4: 1) eluting, prepare the title compound of 19.1g.
1H-NMR(CDCl 3)δ1.48(s，9H)1.84(t，J＝2.3Hz，3H)2.26(t，J＝6.3Hz，1H)3.13-3.17(m，4H)3.53-3.57(m，4H)4.58(q，J＝2.3Hz，2H)4.64(d，J＝6.3Hz，2H)
(f) 4-[1-(2-butyne base)-5-cyano group-4-formoxyl-1H-imidazoles-2-yl] piperazine-1-carboxylic acid tertiary butyl ester
3.28g manganese dioxide is joined 4-[1-(2-butyne base)-5-cyano group-4-hydroxymethyl-1H-imidazoles-2-yl of the 1.35g of 5ml] in the dichloromethane solution of piperazine-1-carboxylic acid tertiary butyl ester.Reaction solution at room temperature stirred 15 hours, and stirring and reflux are 5 hours then.Filtering solution, and concentrating under reduced pressure then.Residue is through the silica gel column chromatography purification.Thereby from the part of ethyl acetate-hexane (2: 3) eluting, prepare the title compound of 1.11g.
1H-NMR(CDCl 3)δ1.50(s，9H)1.88(t，J＝2.3Hz，3H)3.24-3.28(m，4H)3.59-3.63(m，4H)4.70(q，J＝2.3Hz，2H)9.87(s，1H)
(g) 4-[1-(2-butyne base)-5-cyano group-4-(2-ethoxy carbonyl vinyl)-1H-imidazoles-2-yl] piperazine -1-carboxylic acid tertiary butyl ester
Under nitrogen,, the 0.038g sodium hydride is joined in the tetrahydrofuran solution of 0.243g diethyl phosphonyl ethyl acetate of 5ml in 5 ℃.Add 4-[1-(2-butyne the base)-5-cyano group-4-formoxyl-1H-imidazoles-2-yl that is dissolved in the 0.310g in the 5ml oxolane] piperazine-1-carboxylic acid tertiary butyl ester, and with mixture stirring 30 minutes.The 0.1N sodium hydroxide of 50ml ethyl acetate and 25ml is joined in this solution.Organic layer is through dried over mgso, and concentrating under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby from the part of ethyl acetate-hexane (3: 7) eluting, prepare the title compound of 0.380g.
1H-NMR(CDCl 3)δ1.33(t，J＝7.4Hz，3H)1.50(s，9H)1.86(t，J＝2.3Hz，3H)3.19-3.23(m，4H)3.55-3.59(m，4H)4.25(q，J＝7.4Hz，2H)4.59(q，J＝2.3Hz，2H)6.70(d，J＝15.8Hz，1H)7.50(d，J＝15.8Hz，1H)
(h) 4-[1-(2-butyne base)-5-cyano group-4-(2-carboxy vinyl)-1H-imidazoles-2-yl] piperazine-1-carboxylic acid Tertiary butyl ester
According to the method described in the embodiment 338 (d), by using 4-[1-(2-butyne base)-5-cyano group-4-(2-ethoxy carbonyl vinyl)-1H-imidazoles-2-yl] piperazine-1-carboxylic acid tertiary butyl ester, prepare title compound.
1H-NMR(CDCl 3)δ1.50(s，9H)1.86(t，J＝2.3Hz，3H)3.19-3.23(m，4H)3.55-3.59(m，4H)4.59(q，J＝2.3Hz，2H)6.70(d，J＝15.8Hz，1H)7.50(d，J＝15.8Hz，1H)
(i) 4-[1-(2-butyne base)-5-cyano group-4-(2-azido carbonyl ethenyl)-1H-imidazoles-2-yl] piperazine -1-carboxylic acid tertiary butyl ester
Under nitrogen, will contain 4-[1-(2-butyne base)-5-cyano group-4-(2-carboxy vinyl)-1H-imidazoles-2-yl of 0.200g] mixture of the t-butanol solution of the 0.108ml diphenyl phosphoryl azide of piperazine-1-carboxylic acid tertiary butyl ester, 0.073ml triethylamine and 2ml is in 50 ℃ of heating 4 hours.The 50ml ethyl acetate is joined in the solution, and mixture is washed with 20ml.Organic layer is through dried over mgso, and concentrating under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby from the part of ethyl acetate-hexane (2: 3) eluting, prepare the title compound of 0.178g.
1H-NMR(CDCl 3)δ1.48(s，9H)1.86(t，J＝2.2Hz，3H)3.19-3.23(m，4H)3.55-3.59(m，4H)4.59(q，J＝2.2Hz，2H)6.67(d，J＝15.4Hz，1H)7.56(d，J＝15.4Hz，1H)
(i) 4-[4-(2-tert-butoxycarbonyl amido vinyl)-1-(2-butyne base)-5-cyano group-1H-imidazoles-2-yl] Piperazine-1-carboxylic acid tertiary butyl ester
Under nitrogen, with 4-[1-(2-butyne base)-5-cyano group-4-(2-azido (azide) carbonyl ethenyl)-1H-imidazoles-2-yl of the 0.178g of 10ml] the t-butanol solution reflux of piperazine-1-carboxylic acid tertiary butyl ester 15 hours.The concentrating under reduced pressure solvent.Residue is through the silica gel column chromatography purification.Thereby from the part of ethyl acetate-hexane (9: 11) eluting, prepare the title compound of 0.169g.
1H-NMR(CDCl 3)δ1.48(s，9H)1.84(t，J＝2.2Hz，3H)3.16-3.19(m，4H)3.54-3.58(m，4H)4.51(q，J＝2.2Hz，2H)5.83(d，J＝15.0Hz，1H)6.43-6.53(m，1H)7.55-7.66(m，1H)
(k) 4-[4-(2-tert-butoxycarbonyl amido vinyl)-1-(2-butyne base)-5-carbamoyl-1H-miaow Azoles-2-yl] piperazine-1-carboxylic acid tertiary butyl ester
According to the method described in the embodiment 332 (b), by using 4-[4-(2-tert-butoxycarbonyl amido vinyl)-1-(2-butyne base)-5-cyano group-1H-imidazoles-2-yl] piperazine-1-carboxylic acid tertiary butyl ester, prepare title compound.
1H-NMR(CDCl 3)δ1.48(s，9H)1.84(t，J＝2.2Hz，3H)3.21-3.25(m，4H)3.54-3.58(m，4H)4.68(q，J＝2.2Hz，2H)5.90(br.s，1H)6.36(br.d，J＝14.8Hz，1H)6.92(br.d，J＝8.4Hz，1H)7.45(br.s，1H)7.52(m，1H)
(1) 3-(2-butyne base)-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-c] pyridine-4-ketone trifluoroacetic acid also Ester
The 5N hydrochloric acid of 0.1ml is joined 4-[4-(2-tert-butoxycarbonyl amido vinyl)-1-(2-butyne base)-5-carbamoyl-1H-imidazoles-2-yl of the 0.0075g of 0.3ml] in the alcoholic solution of piperazine-1-carboxylic acid tertiary butyl ester, and mixture at room temperature stirred 15 hours.The concentrating under reduced pressure solvent.Residue obtains the title compound of 0.0043g through reversed phase high-performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) purification.
1H-NMR(CD 3OD)δ1.81(t，J＝2.4Hz，3H)3.45-3.48(m，4H)3.62-3.65(m，4H)5.15(q，J＝2.4Hz，2H)6.60(d，J＝7.1Hz，1H)7.18(d，J＝7.1Hz，1H)
MS?m/e(ESI)272.32(MH +-CF 3COOH)
Embodiment 339:
3-(2-butyne base)-5-(2-phenylethyl)-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-c] pyridine-4-also The ketone trifluoro-acetate
(a) 4-[3-(2-butyne base)-4-oxo-4,5-dihydro-3H-imidazo [4,5-c] pyridine-2-yl] piperazine-1- The carboxylic acid tertiary butyl ester
According to the method described in the embodiment 258 (a), by using 3-(2-butyne base)-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-c] pyridine-4-ketone trifluoro-acetate also, prepares title compound.
1H-NMR(CDCl 3)δ1.49(s，9H)1.83(t，J＝2.3Hz，3H)3.35-3.39(m，4H)3.60-3.64(m，4H)5.07(q，J＝2.3Hz，2H)6.55(d，J＝7.1Hz，1H)6.97(d，J＝7.1Hz，1H)
(b) 3-(2-butyne base)-5-(2-phenylethyl)-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-c] pyrrole also Pyridine-4-ketone trifluoro-acetate
According to the method described in the embodiment 258 (b), by using 4-[3-(2-butyne base)-4-oxo-4,5-dihydro-3H-imidazo [4,5-c] pyridine-2-yl] piperazine-1-carboxylic acid tertiary butyl ester and (2-bromoethyl) benzene, prepare title compound.
1H-NMR(CD 3OD)δ1.83(t，J＝2.4Hz，3H)3.05(t，J＝7.3Hz，2H)3.45-3.48(m，4H)3.62-3.65(m，4H)4.26(t，J＝7.3Hz，2H)5.18(q，J＝2.4Hz，2H)6.46(d，J＝7.3Hz，1H)7.15(d，J＝7.3Hz，1H)7.16-7.30(m，5H)
MS?m/e(ESI)376.36(MH +-CF 3COOH)
Embodiment 340:
3-(2-butyne base)-5-(2-phenoxy group ethyl)-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-c] pyridine also -4-ketone trifluoro-acetate
According to the method described in the embodiment 258 (b), by using 4-[3-(2-butyne base)-4-oxo-4,5-dihydro-3H-imidazo [4,5-c] pyridine-2-yl] piperazine-1-carboxylic acid tertiary butyl ester and 2 bromoethyl benzene base ether, prepare title compound.
1H-NMR(CD 3OD)δ1.80(t，J＝2.4Hz，3H)3.45-3.48(m，4H)3.62-3.65(m，4H)4.30(t，J＝5.5Hz，2H)4.44(t，J＝5.5Hz，2H)5.16(q，J＝2.4Hz，2H)6.59(d，J＝6.1Hz，1H)6.87-6.91(m，3H)7.20-7.24(m，2H)7.50(d，J＝6.1Hz，1H)
MS?m/e(ESI)392.34(MH +-CF 3COOH)
Embodiment 341:
3-(2-butyne base)-5-(2-oxo-2-phenylethyl)-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-c] also Pyridine-4-ketone trifluoro-acetate
According to the method described in the embodiment 258 (b), by using 4-[3-(2-butyne base)-4-oxo-4,5-dihydro-3H-imidazo [4,5-c] pyridine-2-yl] piperazine-1-carboxylic acid tertiary butyl ester and 2-bromoacetophenone, prepare title compound.
1H-NMR(CD 3OD)δ1.79(t，J＝2.3Hz，3H)3.46-3.50(m，4H)3.64-3.68(m，4H)5.16(q，J＝2.3Hz，2H)5.61(s，2H)6.65(d，J＝7.3Hz，1H)7.37(d，J＝7.3Hz，1H)7.57(t，J＝8.0Hz，2H)7.69(t，J＝8.OHz，1H)8.10(d，J＝8.0Hz，2H)
MS?m/e(ESI)392.34(MH +-CF 3COOH)
Embodiment 353
7-(2-butyne base)-1,3-dimethyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone
(a) 4-[7-(2-butyne base)-1,3-dimethyl-2,6-dioxo-2.3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine Piperazine-1-carboxylic acid tert-butyl ester
The N that 8-Chlorotheophyline and the 5g potassium carbonate of 4.9g is dissolved in 100mL in the dinethylformamide, and adds the 1-bromo-2-butyne of 2.4mL then.The mixture that generates at room temperature stirred spend the night, and then with the ethyl acetate dilution, and wash with water.Filter and collect the insoluble white solid that generates, and wash, obtain 7-(2-butyne base)-8-chloro-1 of 3.8g, 3-dimethyl-3,7-dihydro purine-2,6-diketone with ethyl acetate.Then, with 7-(2-butyne base)-8-chloro-1 that 1.8g generates, 3-dimethyl-3,7-dihydro purine-2, the 6-diketone mixes with the 1-piperazine carboxylic acid tert-butyl ester of 3.7g, and mixture was stirred one hour down in 150 ℃.After being cooled to room temperature, with the mixture ethyl acetate extraction.The organic layer water is also washed with saturated nacl aqueous solution then, and through anhydrous magnesium sulfate drying.Remove solvent under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby, from part, prepare the 1.6g title compound with hexane-ethyl acetate (1: 4) eluting.
1H-NMR(CDCl 3)δ：1.49(s，9H)1.82(t，J＝2.4Hz，3H)3.33-3.36(m，4H)3.40(s，3H)3.52(s，3H)3.58-3.61(m，4H)4.88(q，J＝2.4Hz，2H)
(b) 7-(2-butyne base)-1,3-dimethyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone
With the 4-[7-(2-butyne base)-1 of 2.5g, 3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the 15mL trifluoroacetic acid.Mixture was stirred under room temperature 30 minutes.Remove solvent under reduced pressure.Then residue (had the silica gel with amido modified surface: column chromatography purification Fuji Silysia Chemical Ltd.NH-DM 2035) by using NH silica gel.Thereby, from part, prepare the 1.6g title compound with eluent ethyl acetate.
1H-NMR(CDCl 3)δ：1.82(t，J＝2.4Hz，3H)3.13-3.16(m，4H)3.40(s，3H)3.46-3.48(m，4H)3.52(s，3H)4.87(q，J＝2.4Hz，2H)
Embodiment 354
7-(2-butyne base)-3-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone
(a) 4-[7-(2-butyne base)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine -1-carboxylic acid tert-butyl ester
The 3-methylxanthine of 1.1g is dissolved in the N of 15mL, in the dinethylformamide, and adds the 1-bromo-2-butyne of 1.0g potassium carbonate and 0.64mL then.The mixture that generates at room temperature stirred spend the night, and then with the ethyl acetate dilution, and wash with water.Filter and collect the insoluble white solid that generates, and wash, obtain 7-(2-butyne base)-3-methyl-3 of 1.3g, 7-dihydro purine-2,6-diketone with ethyl acetate.7-(2-butyne base)-3-methyl-3 that 1.3g is generated subsequently, 7-dihydro purine-2, the 6-diketone is dissolved in the N of 15mL, in the dinethylformamide, and then the N-chloro-succinimide of 0.89g is joined in the mixture simultaneously in cooled on ice.This mixture is at room temperature stirred 3 hours, and then with ethyl acetate dilution and wash with water.Filter and collect the insoluble white solid that generates, and wash, obtain 7-(2-butyne base)-8-chloro-3-methyl-3 of 1.1g, 7-dihydro purine-2,6-diketone with ethyl acetate.7-(2-butyne base)-8-chloro-3-methyl-3 that 1.4g is generated then, 7-dihydro purine-2, the 6-diketone mixes with the 1-piperazine carboxylic acid tert-butyl ester of 2.8g, and with mixture in 150 ℃ times stirrings one hour.Then this mixture is cooled to room temperature, and uses ethyl acetate extraction.The organic layer water is also washed with saturated nacl aqueous solution then, and through anhydrous magnesium sulfate drying.Remove solvent under reduced pressure.Residue is through the silica gel column chromatography purification.Thereby from part, prepare the 1.1g title compound with hexane-ethyl acetate (1: 4) eluting.
1H-NMR(CDCl 3)δ：1.49(s，9H)1.82(t，J＝2.4Hz，3H)3.35-3.37(m，4H)3.47(s，3H)3.58-3.61(m，4H)4.85(q，J＝2.4Hz，2H)7.73(s，1H)
(b) 7-(2-butyne base)-3-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone
By the same procedure described in the embodiment 353-(b), using 4-[7-(2-butyne base)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester prepares title compound.
1H-NMR(CDCl 3)δ：1.82(t，J＝2.4Hz，3H)3.02-3.05(m，4H)3.37-3.39(m，4H)3.48(s，3H)4.85(q，J＝2.4Hz，2H)
Embodiment 355
[7-(2-butyne base)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-yl] second Acid methyl ester trifluoro-acetate
With 4-[7-(2-butyne base)-3-methyl-2 of 15mg, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester and 7mg potassium carbonate be dissolved in the N of 1mL, in the dinethylformamide, and adds 10 μ L methyl bromoacetates then.The mixture that generates at room temperature stirred spend the night, and then with the ethyl acetate dilution and wash with water.Steaming desolventizes, and then residue is dissolved in the 0.5mL trifluoroacetic acid.Mixture was stirred under room temperature 30 minutes.Steaming desolventizes, and comes the HPLC of the reversed-phase column of eluting to carry out purification as solvent by making water-acetonitrile-trifluoroacetic acid the residue of half part (aliquot).Thereby prepare the 6.9mg title compound.
MS?m/e(ESI)375(MH +-CF 3COOH)
Embodiment 356
7-(2-butyne base)-1-(2-ethoxyethyl group)-3-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6- The diketone trifluoro-acetate
According to the same procedure described in the embodiment 355, use 2-bromoethyl ethylether to prepare title compound.
MS?m/e(ESI)375(MH +-CF 3COOH)
Embodiment 357
7-(2-butyne base)-3-methyl-8-(piperazine-1-yl)-1-(2-propynyl)-3,7-dihydro purine-2,6-diketone Trifluoro-acetate
According to the same procedure described in the embodiment 355, use propargyl bromide to prepare title compound.
MS?m/e(ESI)341(MH +-CF 3COOH)
Embodiment 358
1, two (2-butyne the base)-3-methyl-8-(piperazine-1-yl)-3 of 7-, 7-dihydro purine-2,6-diketone trifluoroacetic acid Ester
According to the same procedure described in the embodiment 355, use 1-bromo-2-butyne to prepare title compound.
MS?m/e(ESI)355(MH +-CF 3COOH)
Embodiment 359
[7-(2-butyne base)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-yl] second The nitrile trifluoro-acetate
According to the same procedure described in the embodiment 355, use bromoacetonitrile to prepare title compound.
MS?m/e(ESI)342(MH +-CF 3COOH)
Embodiment 360
7-(2-butyne base)-1-ethyl-3-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoro second Acid esters
According to the same procedure described in the embodiment 355, use iodoethane to prepare title compound.
MS?m/e(ESI)331(MH +-CF 3COOH)
Embodiment 361
7-(2-butyne base)-3-methyl isophthalic acid-[(2-oxo-2-phenyl) ethyl]-8-(piperazine-1-yl)-3, the 7-dihydro is fast Purine-2,6-diketone trifluoro-acetate
According to the same procedure described in the embodiment 355, use the 2-bromoacetophenone to prepare title compound.
MS?m/e(ESI)421(MH +-CF 3COOH)
Embodiment 362
7-(2-butyne base)-1-[2-(4-chlorphenyl)-2-oxoethyl]-3-methyl-8-(piperazine-1-yl)-3, the 7-dihydro Purine-2,6-diketone trifluoro-acetate
According to the same procedure described in the embodiment 355, use 2-bromo-4 '-chloro-acetophenone to prepare title compound.
MS?m/e(ESI)455(MH +-CF 3COOH)
Embodiment 363
7-(2-butyne base)-3-methyl isophthalic acid-(2-phenoxy group ethyl)-8-(piperazine-1-yl)-3,7-dihydro purine-2,6- The diketone trifluoro-acetate
According to the same procedure described in the embodiment 355, use the 2-phenoxyethyl bromide to prepare title compound.
MS?m/e(ESI)423(MH +-CF 3COOH)
Embodiment 364
2-[7-(2-butyne base)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-base Methyl] the benzonitrile trifluoro-acetate
According to the same procedure described in the embodiment 355, use the 2-cyano-benzyl bromide to prepare title compound.
MS?m/e(ESI)418(MH +-CF 3COOH)
Embodiment 365
4-[7-(2-butyne base)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-base Methyl] the essence of Niobe trifluoro-acetate
According to the same procedure described in the embodiment 355, use 4-(bromomethyl) essence of Niobe to prepare title compound.
MS?m/e(ESI)451(MH +-CF 3COOH)
Embodiment 366
3-[7-(2-butyne base)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-base Methyl] the essence of Niobe trifluoro-acetate
According to the same procedure described in the embodiment 355, use 3-(bromomethyl) essence of Niobe to prepare title compound.
MS?m/e(ESI)451(MH +-CF 3COOH)
Embodiment 367
7-(2-butyne base)-3-methyl isophthalic acid-(2-phenylethyl)-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-two The ketone trifluoro-acetate
According to the same procedure described in the embodiment 355, use (2-bromoethyl) benzene to prepare title compound.
MS?m/e(ESI)407(MH +-CF 3COOH)
Embodiment 368
2-[7-(2-butyne base)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1- Base]-N-phenyl acetamide trifluoro-acetate
With 4-[1-carboxymethyl-3-methyl-7-(2-butyne base)-2 of 25mg, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the 1mL oxolane.With 1 of 5 μ L aniline, 9mg, 1-carbonyl dimidazoles and 8 μ L triethylamines join in this mixture then.The mixture that generates was stirred 5 hours down in 60 ℃.With this solution with ethyl acetate dilution and wash with water, and through anhydrous magnesium sulfate drying.Steaming desolventizes, and then residue is dissolved in the 0.5mL trifluoroacetic acid.Mixture was stirred under room temperature 30 minutes.Steaming desolventizes, and with half part residue by making the HPLC purification of water-acetonitrile-trifluoroacetic acid as the reversed-phase column of eluting solvent.Thereby prepare the 2.74mg title compound.
MS?m/e(ESI)436(MH +-CF 3COOH)
Embodiment 369
7-(2-methoxyphenyl)-1,3-dimethyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoro Acetas
(a) 4-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl) piperazine-1-carboxylic acid uncle Butyl ester
8-Chlorotheophyline and 11.69g piperazine-1-carboxylic acid tert-butyl ester of 3.5g are mixed, and under 110 ℃, stir and spend the night.Then with mixture with ethyl acetate and dilute with water then.Filtration is collected the insoluble white solid of generation and is washed with ethyl acetate, obtains the 3.65g title compound.
1H-NMR(CDCl 3)δ：1.48(s，9H)3.38(s，3H)3.54-3.57(m，7H)3.66-3.69(m，4H)11.58(s，1H)
(b) 7-(2-methoxyphenyl)-1,3-dimethyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone three Ethyl fluoroacetate
With the 4-of 11mg (1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl) 2-methoxybenzene ylboronic acid and the 10mg copper acetate (II) of piperazine-1-carboxylic acid tert-butyl ester, 15mg are suspended in the 0.5mL anhydrous tetrahydro furan, and add the 0.1mL pyridine then.The mixture that generates was stirred under room temperature 5 days.Reaction solution is filtered by the short column of filling with NH silica gel, and concentrated filtrate.Residue is dissolved in the 0.5mL trifluoroacetic acid, and mixture was stirred under room temperature 30 minutes.Behind concentrated solvent, the residue that generates is passed through the reversed phase high-performance liquid chromatography purification.Thereby prepare the 3.53mg title compound.
1H-NMR(CDCl 3)δ：3.05-3.20(m，4H)3.29(s，3H)3.50-3.51(m，7H)3.81(s，3H)7.04-7.07(m，2H)7.26-7.30(m，1H)7.47(dt，J＝2.0，8.0Hz，1H)
MS?m/e(ESI)371(MH +-CF 3COOH)
Embodiment 370
7-(2-cyano-phenyl)-1,3-dimethyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoro second Acid esters
(a) 4-[7-(2-formoxyl phenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8- Base] piperazine-1-carboxylic acid tert-butyl ester
With the 4-of 226mg (1,3-dimethyl-2,6-dioxo-2; 3; 6,7-tetrahydrochysene-1H-purine-8-yl) 2-formoxyl phenylboric acid and the 200mg copper acetate (II) of piperazine-1-carboxylic acid tert-butyl ester, 200mg are suspended in the 5mL anhydrous tetrahydro furan, and add the 0.2mL pyridine then.The mixture that generates was stirred under room temperature 5 days.Reaction solution is filtered by the short column of filling with silica gel, and concentrated filtrate.Residue is through the silica gel column chromatography purification.Thereby from part, prepare the 51mg title compound with 1: 1 hexane-eluent ethyl acetate.
1H-NMR(CDCl 3)δ：1.42(s，9H)3.10-3.14(m，4H)3.25-3.34(m，7H)3.60(s，3H)7.53(dd，J＝1.2，8.0Hz，1H)7.63-7.67(m，1H)7.73-7.78(m，1H)8.02-8.04(m，1H)9.86(s，1H)
(b) 7 (2-cyano-phenyls)-1,3-dimethyl-8-(piperazine-1-yl)-3,7--dihydro purine-2,6-diketone trifluoro Acetas
With the 4-[7-(2-formoxyl phenyl)-1 of 13mg, 3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester and 10mg oxammonium hydrochloride. be dissolved in the mixture that contains 1mL ethanol and 0.2mL water.About 10mg potassium acetate is joined in the mixture.The mixture that generates was stirred under room temperature 30 minutes.Reaction solution is diluted with ethyl acetate, and wash with sodium bicarbonate aqueous solution then.Organic layer through anhydrous magnesium sulfate drying, and is filtered then.Concentrating under reduced pressure filtrate obtains 4-[7-[2-(oxyimino methyl) phenyl]-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester.This chemical compound is dissolved in the 0.5mL dichloromethane, and adds about 0.05mL triethylamine and 0.05mL mesyl chloride then.The mixture that generates was stirred under room temperature 0.5 hour.Steaming desolventizes, and residue is dissolved in the trifluoroacetic acid.Concentrated solution, and with residue by the reversed phase high-performance liquid chromatography purification, prepare the 4.14mg title compound.
MS?m/e(ESI)366(MH +-CF 3COOH)
Embodiment 371
7-(2-ethenylphenyl)-1,3-dimethyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoro Acetas
The 9mg potassium tert-butoxide is dissolved in the 1mL oxolane, and adds 31mg Diethylaminoethyl triphenyl phosphonium then.The mixture that generates was stirred under room temperature 30 minutes.The 4-[7-(2-formoxyl phenyl)-1 that will contain 20mg, 3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] the 1mL tetrahydrofuran solution of piperazine-1-carboxylic acid tert-butyl ester joins in this mixture, then it stirred under room temperature 1 hour.With reaction solution with ethyl acetate and dilute with water then.Organic layer through anhydrous magnesium sulfate drying, and is filtered then.Concentrating under reduced pressure filtrate prepares the 4-[7-(2-ethenylphenyl)-1 of 40mg, 3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester.This chemical compound of 12mg is dissolved in the trifluoroacetic acid.Concentrate this solution, and residue is passed through the reversed phase high-performance liquid chromatography purification, prepare the 4.38mg title compound.
MS?m/e(ESI)367(MH +-CF 3COOH)
Embodiment 372
7-(2-chlorphenyl)-1,3-dimethyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone
(a) 7-(2-chlorphenyl)-1,3-dimethyl-3,7-dihydro purine-2,6-diketone
N with 2-chlorophenylboronic acid and the 220mg copper acetate (II) of 510mg theophylline, 1g is suspended in 10mL in the dinethylformamide, and adds the 1mL pyridine then.The mixture that generates at room temperature stirred spend the night.Reaction solution is diluted with ethyl acetate, and wash with 30% ammonia.Organic layer through anhydrous magnesium sulfate drying, and is filtered.Concentrating under reduced pressure filtrate is also ground residue with ether, prepare the 147mg title compound.
1H-NMR(CDCl 3)δ：3.72(s，3H)3.68(s，3H)7.43-7.51(m，3H)7.57-7.60(m，1H)7.68(s，1H)
(b) 8-chloro-7-(2-chlorphenyl)-1,3-dimethyl-3,7-dihydro purine-2,6-diketone
With the 7-(2-chlorphenyl)-1 of 138mg, 3-dimethyl-3,7-dihydro purine-2, the N-chloro-succinimide of 6-diketone and 78mg is suspended in the N of 1mL, in the dinethylformamide.The mixture that generates was stirred under room temperature 2 hours.Reaction solution is diluted with ethyl acetate, and wash with water.Organic layer through anhydrous magnesium sulfate drying, and is filtered then.Concentrating under reduced pressure filtrate prepares the 151mg title compound.
(c) 4-[7-(2-chlorphenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine Piperazine-1-carboxylic acid tert-butyl ester
With the 8-chloro-7-(2-chlorphenyl)-1 of 142mg, 3-dimethyl-3,7-dihydro purine-2, the 6-diketone mixes with piperazine-1-carboxylic acid tert-butyl ester of 500mg.And mixture stirred 4 hours down in 150 ℃, and then with the ethyl acetate dilution and wash with water.Organic layer is also filtered through anhydrous magnesium sulfate drying.Concentrating under reduced pressure filtrate.With residue through the silica gel column chromatography purification.Thereby from the part of hexane-eluent ethyl acetate of 2: 3, prepare the 143mg title compound.
1H-NMR(CDCl 3)δ：1.43(s，9H)3.21-3.23(m，4H)3.30(s，3H)3.31-3.35(m，4H)3.58(s，3H)7.42-7.51(m，3H)7.55-7.57(m，1H)
(d) 7-(2-chlorphenyl)-1,3-dimethyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone
With the 4-[7-(2-chlorphenyl)-1 of 102mg, 3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the 5mL trifluoroacetic acid.The mixture that generates was stirred under room temperature 30 minutes.Steaming desolventizes, and residue is carried out purification by the column chromatography of using NH-silica gel.Thereby from the part of 9: 1 ethyl acetate and methanol-eluted fractions, prepare the 109mg title compound.
1H-NMR(CDCl 3)δ：2.77(dt，J＝1.6，4.8Hz，4H)3.24(t，J＝5.2Hz，4H)3.30(s，3H)3.58(s，3H)7.41-7.44(m，2H)7.48-7.51(m，1H)7.55-7.56(m，1H)
Embodiment 373
7-(2-chlorphenyl)-3-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoro-acetate
(a) 7-benzyl-3-methyl-3,7-dihydro purine-2,6-diketone
The 3-methylxanthine of 2.882g is suspended in the N of 40mL, in the dinethylformamide, and adds 3g potassium carbonate and 2.5mL benzyl bromide a-bromotoluene then.The mixture that generates at room temperature stirred spend the night.Reaction solution is diluted with ethyl acetate, and with the pickling of 1N salt.And filter the crystal of collecting precipitation, and wash with ethyl acetate.Thereby prepare the 3.18g title compound.
1H-NMR(d 6-DMSO)δ：3.32(s，3H)5.42(s，2H)7.27-7.35(m，5H)8.21(s，1H)11.13(s，1H)
(b) 7-benzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene purine-1-ylmethyl 2,2-neopentanoic acid Ester
With 7-benzyl-3-methyl-3 of 3.18g, 7-dihydro purine-2, the 6-diketone is suspended in the N of 40mL, in the dinethylformamide.The chloromethyl pivalate of 2.6g potassium carbonate and 2.15mL is joined in the mixture.The mixture stirring under 40 ℃ that generates is spent the night.Reaction solution is diluted with ethyl acetate, and with the pickling of 1N salt.Organic layer is also filtered through anhydrous magnesium sulfate drying.Concentrating under reduced pressure filtrate.With residue through the silica gel column chromatography purification.Thereby from the part of 1: 3 hexane and eluent ethyl acetate, prepare the 4.26g title compound.
1H-NMR(CDCl 3)δ：1.19(s，9H)3.58(s，3H)5.48(s，2H)6.04(s，2H)7.32-7.39(m，5H)7.58(s，1H)
(c) 3-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene purine-1-ylmethyl 2,2-dimethyl propylene acid esters
With 7-benzyl-3-methyl-2 of 4.26g, 6-dioxo-2,3,6,7-tetrahydrochysene purine-1-ylmethyl 2,2-dimethyl propylene acid esters is dissolved in the 100mL acetic acid, and adds the 10% palladium carbon of 1.5g then.With the mixture that generates under nitrogen atmosphere in stirred overnight at room temperature.With the reaction solution diatomite filtration, and concentrated filtrate, prepare the 2.98g title compound.
1H-NMR(CDCl 3)δ：1.19(s，9H)3.66(s，3H)6.12(s，2H)7.86(s，1H)
(d) 7-(2-chlorphenyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene purine-1-ylmethyl 2,2-diformazan Base-propionic ester
By the same procedure described in the embodiment 372-(a), use 3-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene purine-1-ylmethyl 2,2-dimethyl propylene acid esters prepares title compound.
(e) 8-chloro-7-(2-chlorphenyl)-3-methyl-3,7-dihydro purine-2,6-diketone
With 7-(2-chlorphenyl)-3-methyl-2 of 144mg, 6-dioxo-2,3,6,7-tetrahydrochysene purine-1-ylmethyl 2,2-dimethyl-propionic ester are dissolved in the mixture that contains 2mL methanol and 1mL oxolane, and add the 20mg sodium hydride then.The mixture that generates at room temperature stirred spend the night.Reaction solution is diluted with ethyl acetate, and with the pickling of 1N salt.Organic layer through anhydrous magnesium sulfate drying, and is filtered.Concentrating under reduced pressure filtrate.Residue is ground with ethyl acetate-ether, prepare 7-(2-chlorphenyl)-3-methyl-3 of 72mg, 7-dihydro purine-2,6-diketone.This chemical compound is dissolved in the N of 1mL, in the dinethylformamide, and adds the N-chloro-succinimide of 35mg then.The mixture that generates at room temperature stirred spend the night, and reaction solution is diluted with ethyl acetate, and with the pickling of 1N salt.Organic layer is also filtered through anhydrous magnesium sulfate drying.Concentrating under reduced pressure filtrate prepares the 58mg title compound.
1H-NMR(CDCl 3)δ：3.59(s，3H)7.42(dd，J＝1.6，7.6Hz，1H)7.47(dt，J＝1.6，9.2Hz，1H)7.54(dt，J＝1.6，7.2Hz，1H)7.61(dt，J＝1.6，7.6Hz，1H)7.93(br，1H)
(f) 4-[7-(2-chlorphenyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1- Carboxylic acid tert-butyl ester
With 8-chloro-7-(2-chlorphenyl)-3-methyl-3 of 58mg, 7-dihydro purine-2, the 6-diketone mixes with 1-(tert-butoxycarbonyl) piperazine of 150mg, and mixture was stirred 4 hours down in 150 ℃.Reaction solution is diluted with ethyl acetate, and wash with water.Organic layer through anhydrous magnesium sulfate drying, and is filtered.Concentrating under reduced pressure filtrate.Residue is through the silica gel column chromatography purification.Thereby from part, prepare the 44mg title compound with eluent ethyl acetate.
1H-NMR(CDCl 3)δ：1.41(s，9H)3.17-3.24(m，4H)3.25-3.41(m，4H)3.53(s，3H)7.41-7.51(m，3H)7.55(dd，J＝2.0，7.6Hz，1H)7.66(br，1H)
(g) 7-(2-chlorphenyl)-3-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoro-acetate
With 4-[7-(2-chlorphenyl)-3-methyl-2 of 8mg, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the trifluoroacetic acid, and concentrated solution then.Residue by the reversed phase high-performance liquid chromatography purification, is prepared the 3.86mg title compound.
MS?m/e(ESI)361(MH +-CF 3COOH)
1H-NMR(CDCl 3)δ：2.76-2.79(m，4H)3.23-3.26(m，4H)3.53(s，3H)7.40-7.43(m，2H)7.48-7.53(m，2H)
Embodiment 374
[7-(2-chlorphenyl)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-yl] second Acid methyl ester trifluoro-acetate
With 4-[7-(2-chlorphenyl)-3-methyl-2 of 18mg, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the N of 1mL, in the dinethylformamide, and adds 0.1mL methyl bromoacetate and 10mg potassium carbonate then.The mixture that generates was stirred under room temperature 3 days.Reaction solution is diluted with ethyl acetate, and wash with water.Organic layer is also filtered through anhydrous magnesium sulfate drying.Concentrating under reduced pressure filtrate.Residue is dissolved in the trifluoroacetic acid, and concentrates this solution.Residue prepares the 8.79mg title compound by the reversed phase high-performance liquid chromatography purification.
MS?m/e(ESI)433(MH +-CF 3COOH)
Embodiment 375
[7-(2-chlorphenyl)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-yl] second The nitrile trifluoro-acetate
Embodiment 376
2-[7-(2-chlorphenyl)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-yl] The acetamide trifluoro-acetate
With 4-[7-(2-chlorphenyl)-3-methyl-2 of 18mg, 6-two, oxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the N of 1mL, in the dinethylformamide, and adds 0.1mL bromoacetonitrile and 10mg potassium carbonate then.The mixture that generates was stirred under room temperature 3 days.Reaction solution is diluted with ethyl acetate, and wash with water.Organic layer is also filtered through anhydrous magnesium sulfate drying.Concentrating under reduced pressure filtrate.Residue is dissolved in the 1mL acetonitrile, and adds 0.05mL TMS iodine then.The mixture that generates was stirred under room temperature 1 hour.Then methanol is joined in the mixture.Concentrated reaction solution.Residue by the reversed phase high-performance liquid chromatography purification, is prepared [7-(2-chlorphenyl)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-yl]-acetonitrile trifluoro-acetate [MS m/e (ESI) 400 (MH of 7.43mg +-CF 3And [7-(2-chlorphenyl)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-yl]-acetamide trifluoro-acetate [MS m/e (ESI) 418 (MH of 3.71mg COOH)] +-CF 3COOH)].
Embodiment 377
7-(2-chlorphenyl)-3-methyl isophthalic acid-(2-phenethyl)-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone Trifluoro-acetate
By the same procedure described in the embodiment 374, use the 2-phenethyl bromide, prepare title compound.
MS?m/e(ESI)465(MH +-CF 3COOH)
Embodiment 378
7-(2-chlorphenyl)-3-methyl isophthalic acid-(2-oxo-2-phenylethyl)-8-(piperazine-1-yl)-3,7-dihydro purine -2,6-diketone trifluoro-acetate
By the same procedure described in the embodiment 374, use bromoacetophenone, prepare title compound.
MS?m/e(ESI)479(MH +-CF 3COOH)
Embodiment 379
7-(2-methoxyphenyl)-3-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoroacetic acid Ester
By the same procedure described in the embodiment 373, use 2-methoxybenzene ylboronic acid, prepare title compound.
MS?m/e(ESI)476(MH +-CF 3COOH)
Embodiment 380
[7-(2-methoxyphenyl)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1- Base] the acetonitrile trifluoro-acetate
Embodiment 381
2-[7-(2-methoxyphenyl)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine -1-yl] the acetamide trifluoro-acetate
By same procedure used in embodiment 375 and 376, use 4-[7-(2-methoxyphenyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester, prepare [7-(2-methoxyphenyl)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-yl] acetonitrile trifluoro-acetate [MS m/e (ESI) 396 (MH +-CF 3COOH)] and 2-[7-(2-methoxyphenyl)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-yl] acetamide trifluoro-acetate [MSm/e (ESI) 414 (MH +-CF 3COOH)].
Embodiment 382
7-(2-methoxyphenyl)-3-methyl isophthalic acid-(2-oxo-2-phenylethyl)-8-(piperazine-1-yl)-3, the 7-dihydro Purine-2,6-diketone trifluoro-acetate
By the same procedure described in the embodiment 374, use 4-[7-(2-methoxyphenyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester and 2-bromoacetophenone, prepare title compound.
MS?m/e(ESI)475(MH +-CF 3COOH)
Embodiment 383
7-(2-methoxyphenyl)-3-methyl isophthalic acid-(2-phenylethyl)-8-(piperazine-1-yl)-3,7-dihydro purine -2,6-diketone trifluoro-acetate
By the same procedure described in the embodiment 374, use 4-[7-(2-methoxyphenyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester and (2-bromoethyl) benzene, prepare title compound.
MS?m/e(ESI)461(MH +-CF 3COOH)
Embodiment 384
7-(2-ethenylphenyl)-3-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone
(a) 4-[7-benzyl-1-(2,2-dimethyl propylene acyloxy methyl)-3-methyl-2,6-dioxo-2,3,6,7-four Hydrogen-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
By embodiment 373-(e) with the same procedure (f), use 7-benzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene purine-1-ylmethyl 2,2-dimethyl propylene acid esters prepares title compound.
(b) 4-[1-(2,2-dimethyl propylene acyloxy methyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H- Purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
With 4-[7-benzyl-1-(2,2-dimethyl propylene acyloxy methyl)-3-methyl-2 of 2.227g, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the 100mL acetic acid, and adds the 10% palladium carbon of 1g then.With the mixture that generates under nitrogen atmosphere in stirred overnight at room temperature.Filtering reacting solution.Concentrated filtrate prepares the 1.89g title compound.
1H-NMR(CDCl 3)δ：1.09(s，9H)1.41(s，9H)3.36(s，3H)3.37-3.42(m，4H)3.45-3.50(m，4H)5.82(s，2H)
(c) 4-[1-(2,2-dimethyl propylene acyloxy methyl)-7-(2-ethenylphenyl)-3-methyl-2, the 6-dioxo -2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
By the same procedure described in embodiment 370 and 371, use 4-[1-(2,2-dimethyl propylene acyloxy methyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester, prepare title compound.
1H-NMR(CDCl 3)δ：1.15(s，9H)1.58(s，9H)3.18(br，4H)3.30(br，4H)3.58(s，3H)5.32(d，J＝11.2Hz，1H)5.75(d，J＝17.2Hz，1H)6.39(dd，J＝10.8，17.2Hz，1H)7.34(dd，J＝1.2，7.6Hz，1H)7.40(dt，J＝1.6，7.2Hz，1H)7.46(dt，J＝1.6，7.6Hz，1H)7.69(dd，J＝1.6，8.0Hz，1H)
(d) 7-(2-ethenylphenyl)-3-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone
With 4-[1-(2,2-dimethyl propylene acyloxy methyl)-7-(2-ethenylphenyl)-3-methyl-2 of 187mg, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the 3mL methanol, and adds the 14mg sodium hydride then.The mixture that generates at room temperature stirred spend the night.Reaction solution is neutralized with 1N hydrochloric acid, and use ethyl acetate extraction then.Organic layer is also filtered through anhydrous magnesium sulfate drying.Steaming desolventizes.With residue through the silica gel column chromatography purification.Thereby, from part, prepare the 4-[3-methyl-2 of 108mg, 6-dioxo-7-(2-ethenylphenyl)-2,3,6,7-tetrahydrochysene-1H-purine-8-yl with 3: 2 hexane-eluent ethyl acetates] piperazine-1-carboxylic acid tert-butyl ester.This chemical compound is dissolved in the 2mL trifluoroacetic acid, and concentrates then.With residue NH-silica gel purification.Thereby from part, prepare the title compound of 84mg with 15: 1 ethyl acetate and methanol-eluted fractions.
1H-NMR(CDCl 3)δ：2.73(t，J＝5.2Hz，4H)3.19(t，J＝5.2Hz，4H)3.54(s，3H)5.32(dd，J＝1.2，10.8Hz，1H)5.74(d，J＝0.8，17.6Hz，1H)6.41(dd，J＝10.8，17.2Hz，1H)7.33(dd，J＝1.2，6.0Hz，1H)7.38(dt，J＝1.6，7.6Hz，1H)7.45(dt，J＝1.6，7.6Hz，1H)7.68(dd，J＝1.6，8.0Hz，1H)
Embodiment 385
7-(2-chlorphenyl)-3-ethyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoro-acetate
(a) 2-amino-7-benzyl-1,7-dihydro purine-6-one hydrochloride
The 100g guanosine is suspended in the 500mL dimethyl sulfoxide.Under room temperature, the 100mL benzyl bromide a-bromotoluene is dropped in this suspension.The reactant mixture that generates was stirred under room temperature 4 hours.Then the 250mL concentrated hydrochloric acid is joined in this reaction, and the mixture that generates was stirred under room temperature 30 minutes.This reactant mixture is poured in the 3L methanol, and the mixture stirring is spent the night.Filtering the crystal of collecting precipitation also washes with methanol then.Crystal in 60 ℃ of following air dryings 24 hours, is prepared the 82.5g title compound.
1H-NMR(d6-DMSO)δ：5.23(s，2H)7.32-7.42(m，5H)8.92(s，1H)
(b) 7-benzyl-3,7-dihydro purine-2,6-diketone
2-amino-7-the benzyl-1 that will contain 12.88g, the white suspension of 7-dihydro purine-6-one hydrochloride, 320mL acetic acid and 32mL water stirred 10 minutes in 110 ℃, and stirred 10 minutes in 50 ℃ then.The aqueous solution that then 32mL is contained the 12.88g sodium nitrite drops in the reactant mixture at leisure in 50 ℃.The reactant mixture that generates was stirred 15 hours in 50 ℃.Filter the light brown suspension that generates, prepare the 4.27g title compound.
1H-NMR(d6-DMSO)δ：5.39(s，2H)7.27-7.35(m，5H)8.11(s，1H)10.86(s，1H)11.57(s，1H)
(c) [7-benzyl-3-(2,2-dimethyl-propionyloxy methyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene purine-1- Base] methyl 2,2-dimethyl-propionic ester
The 7-benzyl xanthine of 9.54g is dissolved in the N of 250mL, in the dinethylformamide, and adds 17g potassium carbonate and 14.2mL chloromethyl pivalate then.The mixture stirring under 50 ℃ that generates is spent the night.Reaction solution is diluted with ethyl acetate, and water and the pickling of 1N salt.Organic layer is also filtered through anhydrous magnesium sulfate drying.Steaming desolventizes.With residue through the silica gel column chromatography purification.Thereby from part, prepare the 12.8g title compound with hexane-eluent ethyl acetate of 3: 2.
(d) [3-(2,2-dimethyl propylene acyloxy methyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene purine-1-yl] methyl 2,2-dimethyl propylene acid esters
By the same procedure described in the embodiment 384-(b), use [7-benzyl-3-(2,2-dimethyl propylene acyloxy methyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene purine-1-yl] methyl 2,2-dimethyl propylene acid esters prepares title compound.
(e) [the 7-tetrahydrochysene is fast for 7-(2-chlorphenyl)-3-(2,2-dimethyl propylene acyloxy methyl)-2,6-dioxo-2,3,6 Purine-1-yl] methyl 2,2-dimethyl propylene acid esters
By the same procedure described in the embodiment 373-(d), use [3-(2,2-dimethyl propylene acyloxy methyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene purine-1-yl] methyl 2,2-dimethyl propylene acid esters prepares title compound.
1H-NMR(CDCl 3)δ：1.16(s，9H)1.22(s，9H)5.99(s，2H)6.19(s，2H)7.42-7.52(m，3H)7.58-7.61(m，1H)7.73(s，1H)
(f) 4-[7-(2-chlorphenyl)-1,3-pair-(2,2-dimethyl propylene acyloxy methyl)-2,6-dioxo-2,3,6,7- Tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
By embodiment 373-(e) with the same procedure (f), use [7-(2-chlorphenyl)-3-(2,2-dimethyl propylene acyloxy methyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene purine-1-yl] methyl 2,2-dimethyl propylene acid esters prepares title compound.
1H-NMR(CDCl 3)δ：1.16(s，9H)1.23(s，9H)1.44(s，9H)3.20-3.35(m，4H)3.32-3.37(m，4H)5.92(s，2H)6.09(s，2H)7.41-7.49(m，2H)7.52-7.57(m，2H)
(g) 4-[7-(2-chlorphenyl)-1-(2,2-dimethyl propylene acyloxy methyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene -1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
4-[7-(2-chlorphenyl)-1 with 2.227g, 3-two-(2,2-dimethyl propylene acyloxy methyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in and contains in 10mL oxolane and the 20mL methanol mixture, and add 1 of 0.518mL then, 8-diazabicylo [5,4,0] 11 carbon-7-alkene.The mixture that generates at room temperature stirred spend the night.1N hydrochloric acid is joined in the reaction solution.Filter and collect precipitated solid and the drying that generates, prepare the 1.025g title compound.
1H-NMR(CDCl 3)δ：1.16(s，9H)1.44(s，9H)3.22-3.24(m，4H)3.33-3.35(m，4H)5.90(s，2H)7.43-7.47(m，2H)7.51-7.57(m，2H)8.71(brs，1H)
(h) 7-(2-chlorphenyl)-3-ethyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoro-acetate
With 4-[7-(2-chlorphenyl)-1-(2,2-dimethyl propylene acyloxy methyl)-2 of 8mg, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the N of 0.3mL, in the dinethylformamide, and add 0.05mL iodoethane and 20mg potassium carbonate then.The mixture stirring under 50 ℃ that generates is spent the night.Ethyl acetate is joined in the reaction solution, and mixture is washed with water.Concentrate organic layer.Residue is dissolved in the methanol, and adds the 5mg sodium hydride then.Mixture was stirred under room temperature 3 hours.Reaction solution is neutralized with 1N hydrochloric acid, and use ethyl acetate extraction then.Concentrated solvent.Residue is dissolved in the trifluoroacetic acid, and concentrated solution then.Residue by the reversed phase high-performance liquid chromatography purification, is prepared the 4.49mg title compound.
MS?m/e(ESI)375(MH +-CF 3COOH)
Embodiment 386
7-(2-chlorphenyl)-3-(2-oxo-2-phenethyl)-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone Trifluoro-acetate
By the same procedure described in the embodiment 385-(h), use bromoacetophenone, prepare title compound.
MS?m/e(ESI)465(MH +-CF 3COOH)
Embodiment 387
7-(2-chlorphenyl)-3-(2-oxo-tetrahydrofuran-3-yl)-8-(piperazine-1-yl)-3,7-dihydro purine-2,6- The diketone trifluoro-acetate
Embodiment 388
2-[7-(2-chlorphenyl)-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl]-the 4-hydroxyl The butanoic acid trifluoro-acetate
By the same procedure described in the embodiment 385-(h), use α-bromo-gamma-butyrolacton, prepare 7-(2-chlorphenyl)-3-(2-oxo-tetrahydrofuran-3-yl)-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoro-acetate [MS m/e (ESI) 431 (MH +-CF 3COOH)] and 2-[7-(2-chlorphenyl)-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl]-4 hydroxybutyric acid trifluoro-acetate [MS m/e (ESI) 449 (MH +-CF 3COOH)].
Embodiment 389
2-[7-(2-chlorphenyl)-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] acetamide Trifluoro-acetate
By the same procedure described in the embodiment 385-(h), use the 2-acetbromamide, prepare title compound.
1H-NMR(d 6-DMSO)δ：2.97-3.04(m，4H)3.22-3.34(m，4H)4.43(s，2H)7.18(brs，1H)7.49-7.59(m，2H)7.62(s，1H)7.66-7.71(m，2H)10.90(s，1H)
MS?m/e(ESI)404(MH +-CF 3COOH)
Embodiment 390
[7-(2-chlorphenyl)-1-methyl-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] second The acid trifluoroacetic acid ester
(a) 4-[7-(2-chlorphenyl)-3-carboxymethyl-1-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8- Base] piperazine-1-carboxylic acid tert-butyl ester
With 4-[7-(2-chlorphenyl)-3-methoxycarbonyl methyl isophthalic acid-methyl-2 of 87mg, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the 2mL methanol, and adds the 5N-sodium hydrate aqueous solution of 0.2mL then.The mixture that generates was stirred under room temperature 2 hours, and then with the neutralization of 1N hydrochloric acid.With the mixture ethyl acetate extraction.Organic layer through anhydrous magnesium sulfate drying, and is filtered.Steaming desolventizes, and prepares title compound.
(b) [7-(2-chlorphenyl)-1-methyl-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] The acetic acid trifluoro-acetate
With 4-[7-(2-chlorphenyl)-3-carboxymethyl-1-methyl-2 of 26mg, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-the 1-carboxylic acid tert-butyl ester is dissolved in the trifluoroacetic acid, and enriched mixture.Residue by the reversed phase high-performance liquid chromatography purification, is prepared the 10.73mg title compound.
1H-NMR(d 6-DMSO)δ：3.15-3.18(m，4H)3.26(s，3H)3.46-3.49(m，4H)4.80(s，2H)7.50-7.59(m，2H)7.63-7.68(m，2H)
MS?m/e(ESI)419(MH +-CF 3COOH)
Embodiment 391
2-[7-(2-chlorphenyl)-1-methyl-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] The acetamide trifluoro-acetate
(a) 4-[7-(2-chlorphenyl)-3-acetamide-1-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8- Base] piperazine-1-carboxylic acid tert-butyl ester
With 4-[7-(2-chlorphenyl)-3-carboxymethyl-1-methyl-2 of 53mg, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the 1mL oxolane, and adds 0.03mL triethylamine and 0.015mL chlorine ethyl carbonate then.The mixture that generates was stirred under room temperature 15 minutes, and add 30% ammonia aqueous solution of 0.1mL then.Reaction solution is diluted with ethyl acetate, and water and the pickling of 1N salt.Organic layer is also filtered through anhydrous magnesium sulfate drying.Steaming desolventizes, and prepares the 53mg title compound.
(b) 2-[7-(2-chlorphenyl)-1-methyl-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3- Base] the acetamide trifluoro-acetate
With 4-[7-(2-chlorphenyl)-3-acetamide-1-methyl-2 of 53mg, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the trifluoroacetic acid, and concentrated this solution.Residue by the reversed phase high-performance liquid chromatography purification, is prepared the 23.31mg title compound.
1H-NMR(d 6-DMSO)δ：3.15-3.18(m，4H)3.26(s，3H)3.45-3.48(m，4H)4.76(s，2H)7.50-7.59(m，2H)7.62-7.68(m，2H)
MS?m/e(ESI)418(MH +-CF 3COOH)
Embodiment 392
[7-(2-chlorphenyl)-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] acetic acid trifluoro Acetas
By embodiment 390-(a) with the same procedure (b), use 4-[7-(2-chlorphenyl)-3-methoxycarbonyl methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester, prepare title compound.
MS?m/e(ESI)405(MH +-CF 3COOH)
Embodiment 393
[7-(2-chlorphenyl)-2,6-dioxo-1-phenethyl-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] The acetic acid trifluoro-acetate
By embodiment 390-(a) with the same procedure (b), use 4-[7-(2-chlorphenyl)-3-methoxycarbonyl methyl-2,6-dioxo-1-phenethyl-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester, prepare title compound.
MS?m/e(ESI)509(MH +-CF 3COOH)
Embodiment 394
2-[7-(2-chlorphenyl)-2,6-dioxo-1-phenethyl-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3- Base] the acetamide trifluoro-acetate
By embodiment 391-(a) with the same procedure (b), use 4-[7-(2-chlorphenyl)-3-carboxymethyl-2,6-dioxo-1-phenethyl-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester, prepare title compound.
MS?m/e(ESI)508(MH +-CF 3COOH)
Embodiment 395
[7-(2-chlorphenyl)-1-methyl-8-(piperazine-1-yl)]-3,7-dihydro purine-2,6-diketone trifluoro-acetate
(a) [7-benzyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2,2-dimethyl propylene acid esters
The 7-benzyl xanthine of 8.66g is dissolved in the N of 300mL, in the dinethylformamide, and adds 1.57g sodium hydride and 7.7mL chloromethyl pivalate then.The mixture that generates at room temperature stirred spend the night.Reaction solution is diluted with ethyl acetate, and water and the pickling of 1N salt then.Organic layer through anhydrous magnesium sulfate drying, and is filtered.Steaming desolventizes.With residue through the silica gel column chromatography purification.Thereby from part, prepare the 2.66g title compound with 1: 1 hexane-eluent ethyl acetate.
1H-NMR(CDCl 3)δ：1.18(s，9H)5.45(s，2H)6.06(s，2H)7.34-7.39(m，5H)7.58(s，1H)8.18(s，1H)
(b) [7-benzyl-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2, the 2-dimethyl propylene Acid esters
With [7-benzyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2 of 2.66g, 2-dimethyl propylene acid esters is dissolved in the N of 30mL, in the dinethylformamide, and adds 1.6g potassium carbonate and 1mL iodomethane then.The mixture that generates at room temperature stirred spend the night.Reaction solution is diluted with ethyl acetate, and water and the pickling of 1N salt.Organic layer is also filtered through anhydrous magnesium sulfate drying.Steaming desolventizes.Residue is ground with toluene, prepare the 2.16g title compound.
1H-NMR(CDCl 3)δ：1.18(s，9H)3.41(s，3H)5.49(s，2H)6.11(s，2H)7.26-7.39(m，5H)7.57(s，1H)
(c) [1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2,2-dimethyl propylene acid esters
By the same procedure described in the embodiment 385-(d), use [7-benzyl-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2,2-dimethyl propylene acid esters prepares the 2.16g title compound.
1H-NMR(CDCl 3)δ：1.19(s，9H)3.48(s，3H)6.17(s，2H)7.83(s，1H)
(d) [7-(2-chlorphenyl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2, the 2-diformazan The base propionic ester
By the same procedure described in the embodiment 385-(e), use [1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2,2-dimethyl propylene acid esters prepares title compound.
(e) 4-[7-(2-chlorphenyl)-3-(2,2-dimethyl-propionyloxy methyl)-1-methyl-2, the 6-dioxo -2,3,6,7-tetrahydrochysene-1H-purine-8-base 1 piperazine-1-carboxylic acid tert-butyl ester
By the same procedure described in the embodiment 385-(f), use [7-(2-chlorphenyl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2,2-dimethyl propylene acid esters prepares title compound.
(f) 4-[7-(2-chlorphenyl)-1-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1- Carboxylic acid tert-butyl ester
By the same procedure described in the embodiment 373-(e), use 4-[7-(2-chlorphenyl)-3-(2,2-dimethyl-propionyloxy methyl)-1-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester, prepare title compound.
1H-NMR(d 6-DMSO)δ：1.35(s，9H)3.04(s，3H)3.06-3.12(m，4H)3.17-3.22(m，4H)7.48(dt，J＝1.6，7.6Hz，1H)7.53(dt，J＝2.0，7.6Hz，1H)7.63(dd，J＝2.0，8.0Hz，1H)7.65(dd，J＝1.6，8.0Hz，1H)
(g) 7-(2-chlorphenyl)-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoro-acetate
By the same procedure described in the embodiment 391-(b), use 4-[7-(2-chlorphenyl)-1-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester, prepare title compound.
1H-NMR(d 6-DMSO)δ：2.95-3.03(m，4H)3.14(s，3H)3.23-3.34(m，4H)7.49-7.62(m，2H)7.66-7.71(m，2H)10.90(s，1H)
MS?m/e(ESI)361(MH +-CF 3COOH)
Embodiment 396
7-(2-butyne base)-3-ethyl-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoro second Acid esters
(a) [7-(2-butyne base)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2, the 2-diformazan The base propionic ester
With [1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2 of 1.871g, 2-dimethyl propylene acid esters is dissolved in the N of 30mL, in the dinethylformamide, and adds the 2-butyne base bromine of 1.5g potassium carbonate and 0.7mL then.The mixture that generates at room temperature stirred spend the night.Reaction solution is diluted with ethyl acetate, and water and the pickling of 1N salt.Organic layer is also filtered through anhydrous magnesium sulfate drying.Steaming desolventizes.With residue through the silica gel column chromatography purification.Thereby from part, prepare the 2.12g title compound with hexane-eluent ethyl acetate of 3: 2.
(b) 7-(2-butyne base)-1-methyl-3,7-dihydro purine-2,6-diketone
By the same procedure described in the embodiment 395-(f), use [7-(2-butyne base)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2,2-dimethyl propylene acid esters prepares title compound.
1H-NMR(CDCl 3)δ：1.91(t，J＝2.4Hz，3H)3.39(s，3H)5.10(s，2H)7.93(s，1H)10.62(s，1H)
( C) 4-[7-(2-butyne base)-1-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine -1-carboxylic acid tert-butyl ester
By the same procedure described in the embodiment 395-(e), use 7-(2-butyne base)-1-methyl-3,7-dihydro purine-2, the 6-diketone prepares title compound.
1H-NMR(CDCl 3)δ：1.48(s，9H)1.83(t，J＝2.4Hz，3H)3.37(s，3H)3.37-3.39(m，4H)3.58-3.60(m，4H)4.87(s，2H)9.68(s，1H)
(d) 7-(2-butyne base)-3-ethyl-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone three Ethyl fluoroacetate
By the same procedure described in the embodiment 385-(h), use 4-[7-(2-butyne base)-1-methyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester, prepare title compound.
MS?m/e(ESI)331(MH +-CF 3COOH)
Embodiment 397
7-(2-butyne base)-3-benzyl-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoro second Acid esters
By the same procedure described in the embodiment 396-(d), use benzyl bromide a-bromotoluene, prepare title compound.
1H-NMR(CDCl 3)δ：1.83(t，J＝2.4Hz，3H)3.03-3.06(m，4H)3.38(s，3H)3.38-3.41(m，4H)4.84(q，J＝2.4Hz，2H)5.21(s，2H)7.26-7.30(m，3H)7.52-7.54(m，2H)
MS?m/e(ESI)393(MH +-CF 3COOH)
Embodiment 398
[7-(2-butyne base)-1-methyl-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] second Acid methyl ester trifluoro-acetate
By the same procedure described in the embodiment 396-(d), use methyl bromoacetate, prepare title compound.
1H-NMR(CDCl 3)δ：1.84(t，J＝2.4Hz，3H)3.00-3.03(m，4H)3.34-3.36(m，4H)3.40(s，3H)3.79(s，3H)4.78(s，2H)4.84(q，J＝2.4Hz，2H)
MS?m/e(ESI)375(MH +-CF 3COOH)
Embodiment 399
7-(2-butyne base)-3-cyclobutyl-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoro Acetas
With 4-[7-(2-butyne base)-1-methyl-2 of 8mg, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the N of 0.4mL, in the dinethylformamide, and adds 10mg potassium carbonate and 0.01mL cyclobutyl bromine then.The mixture stirring under 50 ℃ that generates is spent the night.Reaction solution is diluted with ethyl acetate.Concentrate organic layer.Residue is dissolved in the trifluoroacetic acid, and concentrates this solution.Residue by the reversed phase high-performance liquid chromatography purification, is prepared the 3.72mg title compound.
MS?m/e(ESI)357(MH +-CF 3COOH)
Embodiment 400
7-(2-butyne base)-3-(2-tetrahydrofuran base) methyl isophthalic acid-methyl-8-(piperazine-1-yl)-3,7-dihydro purine -2,6-diketone trifluoro-acetate
By the same procedure described in the embodiment 399, use 2-bromomethyl oxolane, prepare title compound.
1H-NMR(CDCl 3)δ：1.70-1.77(m，1H)1.84(t，J＝2.4Hz，3H)1.88-1.93(m，1H)1.97-2.06(m，2H)3.01-3.04(m，4H)3.34-3.36(m，4H)3.39(s，3H)3.77(dd，J＝8.4，14.0Hz，1H)3.92-3.97(m，2H)4.19(dd，J＝8.4，13.6Hz，1H)4.45-4.50(m，1H)4.83(q，J＝2.4Hz，2H)
MS?m/e(ESI)387(MH +-CF 3COOH)
Embodiment 401
2-[7-(2-butyne base)-1-methyl-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] The acetamide trifluoro-acetate
By the same procedure described in the embodiment 399, use the 2-acetbromamide, prepare title compound.
1H-NMR(CDCl 3)δ：1.68(t，J＝2.4Hz，3H)3.15-3.19(m，4H)3.23(s，3H)3.46-3.51(m，4H)4.55(s，2H)4.71(q，J＝2.4Hz，2H)6.00(br，1H)6.91(br，1H)
MS?m/e(ESI)360(MH +-CF 3COOH)
Embodiment 402
[7-(2-butyne base)-1-methyl-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] benzene Guanidine-acetic acid methyl ester trifluoro-acetate
By the same procedure described in the embodiment 399, use 2-bromophenyl methyl acetate, prepare title compound.
1H-NMR(CDCl 3)δ：1.83(t，J＝2.4Hz，3H)3.02-3.05(m，4H)3.36-3.38(m，4H)3.37(s，3H)3.80(s，3H)4.82(q，J＝2.4Hz，2H)6.50(s，1H)7.30-7.32(m，3H)7.65-7.67(m，2H)
MS?m/e(ESI)451(MH +-CF 3COOH)
Embodiment 403
7-(2-butyne base)-3-propyl group-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoro second Acid esters
By the same procedure described in the embodiment 399, use iodopropane, prepare title compound.
MS?m/e(ESI)345(MH +-CF 3COOH)
Embodiment 404
7-(2-butyne base)-3-(2-oxo-2-phenethyl)-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine -2,6-diketone trifluoro-acetate
By the same procedure described in the embodiment 399, use bromoacetophenone, prepare title compound.
1H-NMR(CDCl 3)δ：1.85(t，J＝2.4Hz，3H)2.96-2.99(m，4H)3.28-3.31(m，4H)3.41(s，3H)4.85(q，J＝2.4Hz，2H)5.48(s，2H)7.50-7.54(m，2H)7.61-7.65(m，1H)8.02-8.05(m，2H)
MS?m/e(ESI)421(MH +-CF 3COOH)
Embodiment 405
2-[7-(2-butyne base)-1-methyl-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] The ethyl propionate trifluoro-acetate
By the same procedure described in the embodiment 399, use the 2 bromopropionic acid ethyl ester, prepare title compound.
1H-NMR(CDCl 3)δ：1.23(t，J＝7.2Hz，3H)1.70(d，J＝7.2Hz，3H)1.84(t，J＝2.4Hz，3H)3.00-3.03(m，4H)3.33-3.37(m，4H)3.38(s，3H)4.15-4.25(m，2H)4.85(q，J＝2.4Hz，2H)5.43(q，J＝7.2Hz，1H)
MS?m/e(ESI)403(MH +-CF 3COOH)
Embodiment 406
7-(2-butyne base)-3-(2-oxo-oxolane-3-yl)-1-methyl-8-(piperazine-1-yl)-3, the 7-dihydro is fast Purine-2,6-diketone trifluoro-acetate
By the same procedure described in the embodiment 399, use α-bromo-gamma-butyrolacton, prepare title compound.
1H-NMR(CDCl 3)δ：1.84(t，J＝2.4Hz，3H)2.59-2.68(m，1H)2.69-2.91(m，1H)3.01-3.03(m，4H)3.34-3.37(m，5H)3.38(s，3H)4.39-4.45(m，1H)4.68(dt，J＝2.8，9；2Hz，2H)4；84(br，2H)
MS?m/e(ESI)387(MH +-CF 3COOH)
Embodiment 407
7-(2-butyne base)-3-(2-ethoxyethyl group)-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6- The diketone trifluoro-acetate
By the same procedure described in the embodiment 399, use the 2-ethoxy ethyl bromide, prepare title compound.
1H-NMR(CDCl 3)δ：1.16(t，J＝7.2Hz，3H)1.83(t，J＝2.4Hz，3H)3.01-3.06(m，4H)3.33-3.46(m，4H)3.39(s，3H)3.58(q，J＝7.2Hz，2H)3.77(t，J＝6.0Hz，2H)4.26(t，J＝6.0Hz，2H)4.85(q，J＝2.4Hz，2H)
MS?m/e(ESI)375(MH +-CF 3COOH)
Embodiment 408
7-(2-butyne base)-3-isopropyl-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone trifluoro Acetas
By the same procedure described in the embodiment 399, use 2-iodopropane, prepare title compound.
MS?m/e(ESI)345(MH +-CF 3COOH)
Embodiment 409
7-(2-butyne base)-3-(3,3-dimethyl-2-oxo butyl)-methyl-8-(piperazine-1-yl)-3, the 7-dihydro Purine-2,6-diketone trifluoro-acetate
By the same procedure described in the embodiment 399, use 1-bromine pinacoline to prepare title compound.
MS?m/e(ESI)401(MH +-CF 3COOH)
Embodiment 410
7-(2-butyne base)-1-methyl-3-(2-oxo-pyrrolidine-3-yl)-8-(piperazine-1-yl)-3,7-dihydro purine -2,6-diketone hydrochloride
By the same procedure described in the embodiment 399, use 3-bromo-2-oxo-pyrrolidine, prepare title compound.
1H-NMR(d6-DMSO)δ：1，80(t，J＝2Hz，3H)2.32-2.48(m，2H)3.17(s，3H)3.20-3.55(m，10H)4.96(q，J＝2Hz，2H)5.14(t，J＝10Hz)7.94(brs，1H)9.04(brs，2H)
Embodiment 411
7-(2-butyne base)-3-(2-ethoxyethyl group)-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone three Ethyl fluoroacetate
(a) 4-[7-(2-butyne base)-1,3-pair-(2,2-dimethyl propylene acyloxy methyl)-2,6-dioxo-2,3,6,7- Tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
To contain 1.0g [3-(2,2-dimethyl propylene acyloxy methyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene purine-1-yl] methyl 2, the N of 1-bromo-2-butyne, 0.73g Anhydrous potassium carbonate and the 15mL of 2-dimethyl propylene acid esters, 0.28mL, the mixture of dinethylformamide stirred under room temperature 2 hours.Reaction solution is extracted with ethyl acetate-water.Organic layer water and saturated nacl aqueous solution are washed, and then through anhydrous magnesium sulfate drying.This liquid of concentrating under reduced pressure.Residue through using the silica gel column chromatography purification of 20-30% ethyl acetate/hexane, is prepared [the 7-(2-butyne base)-3-(2,2-dimethyl propylene acyloxy methyl)-2 of 1.06g, 6-dioxo-2,3,6,7-tetrahydrochysene purine-1-yl] methyl 2,2-dimethyl propylene acid esters.
With chemical compound and the N-chloro-succinimide of 390mg and the N of 5mL that all measures, dinethylformamide mixes.Mixture was stirred under room temperature 1 hour.Reaction solution is extracted with ethyl acetate-water.Organic layer water and saturated nacl aqueous solution are washed, and then through anhydrous magnesium sulfate drying.This liquid of concentrating under reduced pressure.Residue through using the silica gel column chromatography purification of 20-30% ethyl acetate/hexane, is prepared [the 7-(2-butyne base)-8-chloro-3-(2,2-dimethyl propylene acyloxy methyl)-2 of 1.18g, 6-dioxo-2,3,6,7-tetrahydrochysene purine-1-yl] methyl 2,2-dimethyl propylene acid esters.
The chemical compound of all measuring is mixed with 1.4g piperazine-1-carboxylic acid tert-butyl ester, and mixture is stirred down in 150 ℃ in oil bath, stirred simultaneously 30 minutes.Reaction solution by using the silica gel column chromatography purification of 20-30% ethyl acetate/hexane, is prepared the 1.34g title compound.
1H-NMR(CDCl 3)δ：1.18(s，18H)1.49(s，9H)1.84(t，J＝2Hz，3H)3.36(t，J＝5Hz，4H)3.58(t，J＝5Hz)4.86(q，J＝2Hz，2H)6.02(s，2H)，6.03(s，2H)
(b) 4-[7-(2-butyne base)-1-(2,2-dimethyl propylene acyloxy methyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene -1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
4-[7-(2-butyne base)-1 with 0.63g, 3-two-(2,2-dimethyl propylene acyloxy methyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the mixed solvent of 4mL oxolane and 2mL methanol, and adds 0.18mL diazabicylo [5.4.0] endecatylene then.The mixture that generates at room temperature stirred spend the night.Concentrated reaction solution.With residue through the silica gel column chromatography purification.Thereby from part, prepare the 0.29g title compound with hexane-ethyl acetate (1: 5) eluting.
1H-NMR(CDCl 3)δ：1.19(s，9H)1.48(s，9H)1.83(t，J＝2.4Hz，3H)3.37-3.39(m，4H)3.58-3.60(m，4H)4.86(q，J＝2.4Hz，2H)6.00(s，2H)9.08(s，1H)
(c) 7-(2-butyne base)-3-(2-ethoxyethyl group)-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone Trifluoro-acetate
4-[7-(2-butyne base)-1-(2 with 50mg, 2-dimethyl propylene acyloxy methyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester and 15mg potassium carbonate be dissolved in the N of 1.2mL, in the dinethylformamide, and adds the 2-bromoethyl ethylether of 12 μ L then.The mixture that generates was stirred 2 hours down in 60 ℃, and then with the ethyl acetate dilution and wash with water.With liquid through anhydrous magnesium sulfate drying.Concentrate organic layer.With residue through the silica gel column chromatography purification.Thereby from part, prepare 4-[7-(2-butyne base)-1-(2 with hexane-ethyl acetate (2: 1) eluting, 2-dimethyl propylene acyloxy methyl)-and 3-(2-ethoxyethyl group)-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester.Then, with 4-[7-(2-butyne the base)-1-(2 that generates, 2-dimethyl propylene acyloxy methyl)-3-(2-ethoxyethyl group)-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the mixed solvent of 1.0mL oxolane and 0.5mL methanol, and adds the 5mg sodium hydride then.The mixture that generates was stirred under room temperature 1 hour.Reaction solution is neutralized with 2N hydrochloric acid, and use ethyl acetate extraction.Then with organic layer through anhydrous magnesium sulfate drying.Steaming desolventizes and prepares 4-[7-(2-butyne base)-3-(2-ethoxyethyl group)-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester.With 1/4 normal 4-[7-(2-butyne the base)-3-(2-ethoxyethyl group)-2 that generates, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the 0.5mL trifluoroacetic acid, and mixture stirred under room temperature 30 minutes.Steaming desolventizes.Residue with half part carries out purification by making water-acetonitrile-trifluoroacetic acid as the HPLC of the reversed-phase column of eluting solvent then, prepares the 3.2mg title compound.
MS?m/e(ESI)361(MH +-CF 3COOH)
Embodiment 412
[the 7-tetrahydrochysene is fast for 7-(2-butyne base)-3-(2-ethoxyethyl group)-2,6-dioxo-8-(piperazine-1-yl)-2,3,6 Purine-1-yl] the methyl acetate trifluoro-acetate
With resulting 4-[7-(2-butyne base) among the 1/4 normal embodiment 411-(c)-3-(2-ethoxyethyl group)-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester and 7mg potassium carbonate be dissolved in the N of 0.8mL, in the dinethylformamide, and add 10 μ L methyl bromoacetates then.The mixture that generates at room temperature stirred spend the night, and then with the ethyl acetate dilution and wash with water.With this liquid through anhydrous magnesium sulfate drying.Concentrate organic layer, and then residue is dissolved in the 0.5mL trifluoroacetic acid.Mixture was stirred under room temperature 30 minutes.Steaming desolventizes, and the residue of half part is carried out purification by making water-acetonitrile-trifluoroacetic acid as the HPLC of the reversed-phase column of eluting solvent, prepares the 3.2mg title compound.
MS?m/e(ESI)433(MH +-CF 3COOH)
Embodiment 413
7-(2-butyne base)-3-(2-ethoxyethyl group)-1-(2-oxo-2-phenylethyl-8-(piperazine-1-yl)-3,7- Dihydro purine-2,6-diketone trifluoro-acetate
By the same procedure described in the embodiment 412, use the 2-bromoacetophenone, prepare title compound.
MS?m/e(ESI)479(MH +-CF 3COOH)
Embodiment 414
[the 7-tetrahydrochysene is fast for 7-(2-butyne base)-1-(2-ethoxyethyl group)-2,6-dioxo-8-(piperazine-1-yl)-1,2,6 Purine-3-yl] the methyl acetate trifluoro-acetate
(a) 4-[7-(2-butyne base)-3-(2,2-dimethyl propylene acyloxy methyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene -1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
With the 4-[7-(2-butyne base)-2 of 1.1g, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester and 0.43g potassium carbonate be dissolved in the N of 15mL, in the dinethylformamide.On ice 0.60mL chloromethyl pivalate is joined in this mixture then.The mixture that generates at room temperature stirred spend the night, and then with the ethyl acetate dilution and wash with water.Filter and collect the insoluble white solid that generates, and wash, prepare the 0.57g title compound with the mixed solvent of hexane and ethyl acetate (1: 1).
1H-NMR(CDCl 3)δ：1.18(s，9H)1.49(s，9H)1.83(t，J＝2.4Hz，3H)3.33-3.36(m，4H)3.57-3.59(m，4H)4.84(q，J＝2.4Hz，2H)5.99(s，2H)7.72(s，1H)
(b) [7-four for 7-(2-butyne base)-1-(2-ethoxyethyl group)-2,6-dioxo-8-(piperazine-1-yl)-1,2,6 Hydrogen purine-3-yl] the methyl acetate trifluoro-acetate
4-[7-(2-butyne base)-3-(2 with 40mg, 2-dimethyl propylene acyloxy methyl)-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester and 17mg potassium carbonate be dissolved in the N of 1.5mL, in the dinethylformamide, and adds the 2-bromoethyl ethylether of 14 μ L then.The mixture that generates was stirred 5 hours down in 60 ℃, and then with the ethyl acetate dilution and wash with water.With this liquid through anhydrous magnesium sulfate drying.Steaming desolventizes, and with residue through the silica gel column chromatography purification.Thereby from part, prepare 4-[7-(2-butyne base)-3-(2 with hexane-ethyl acetate (1: 1) eluting, 2-dimethyl propylene acyloxy methyl)-and 1-(2-ethoxyethyl group)-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester.Then with 4-[7-(2-butyne the base)-3-(2 that generates, 2-dimethyl propylene acyloxy methyl)-1-(2-ethoxyethyl group)-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the mixed solvent of 1.0mL oxolane and 0.5mL methanol, and adds the 5mg sodium hydride then.The mixture that generates was stirred under room temperature 1 hour.Reaction solution is neutralized with 2N hydrochloric acid, and use ethyl acetate extraction.Then, organic layer through anhydrous magnesium sulfate drying, and is steamed and to desolventize.The residue that generates is dissolved in the N of 1mL, in the dinethylformamide, and adds 10mg potassium carbonate and 10 μ L methyl bromoacetates then.The mixture that generates was stirred under room temperature 2 hours, and dilute with ethyl acetate then and wash with water.Concentrate organic layer, and residue is dissolved in the 0.5mL trifluoroacetic acid.The mixture that generates was stirred under room temperature 30 minutes.Steaming desolventizes, and then the residue of half part is carried out purification by making water-acetonitrile-trifluoroacetic acid as the HPLC of the reversed-phase column of eluant, prepares the 6.2mg title compound.
MS?m/e(ESI)433(MH +-CF 3COOH)
Embodiment 415
[7-(2-butyne base)-2,6-dioxo-1-(2-oxo-2-phenylethyl)-8-(piperazine-1-yl)-1,2,6,7- Tetrahydrochysene purine-3-yl] the methyl acetate trifluoro-acetate
By the same procedure described in the embodiment 414, use the 2-bromoacetophenone, prepare title compound.
MS?m/e(ESI)479(MH +-CF 3COOH)
Embodiment 416
[7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine -3-yl] the ethyl acetate hydrochloride
(a) (7-benzyl-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl) ethyl acetate
The 7-benzyl-3 that will contain 3.0g, 7-dihydro purine-2, the N of 6-diketone, 2.0g Anhydrous potassium carbonate and 60mL, the mixture of dinethylformamide stir down in 40 ℃ in oil bath, and add the 1.5g bromoacetate then.The mixture that generates was stirred 4 hours in 40 ℃.Reaction solution is diluted with ethyl acetate and water, and use ethyl acetate extraction.Organic layer water and saturated nacl aqueous solution are washed, and then through anhydrous magnesium sulfate drying.This liquid of concentrating under reduced pressure.Residue through using the silica gel column chromatography purification of 20-40% (2-propanol/ethyl acetate of 20%)/hexane, is prepared the 1.3g title compound.
1H-NMR(CDCl 3)δ：1.28(t，J＝7Hz，3H)4.23(q，J＝7Hz，2H)4.78(s，2H)5.04(s，2H)7.31-7.39(m，5H)7.51(s，1H)8.01(br.s，1H)
(b) [7-benzyl-1-(2-phenylethyl)-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] ethyl acetate
(7-benzyl-2,6-dioxo-1,2,6, the 7-tetrahydrochysene purine-3-yl) ethyl acetate, 250mg Anhydrous potassium carbonate, the 2 bromoethyl benzene of 0.25mL and the N of 5mL that contain 300mg, the mixture of dinethylformamide stirred 2 hours in 50 ℃ in oil bath.Reaction solution is diluted with ethyl acetate and water, and use ethyl acetate extraction.Organic layer water and saturated nacl aqueous solution are washed, and then through anhydrous magnesium sulfate drying.This liquid of concentrating under reduced pressure.Residue through using the silica gel column chromatography purification of 10-20% (2-propanol/ethyl acetate of 20%)/hexane, is prepared the 366mg title compound.
1H-NMR(CDCl 3)δ：1.29(t，J＝7Hz，3H)2.95(t，J＝8Hz，2H)4.22(t，J＝8Hz，2H)4.24(q，J＝7Hz，2H)4.83(s，2H)5.48(s，2H)7.17-7.39(m，10H)7.49(s，1H)
(c) [7-(2-butyne base)-8-chloro-1-(2-phenylethyl)-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] Ethyl acetate
10% palladium carbon of catalytic amount is joined in [7-benzyl-1-(2-phenylethyl)-2,6-dioxo-1,2,6, the 7-tetrahydrochysene purine-3-yl] ethyl acetate and 10mL acetate mixture that contains 366mg.And with the mixture that generates under nitrogen atmosphere in stirred overnight at room temperature.After removing by filter catalyst, this liquid of concentrating under reduced pressure prepares the residue of 320mg.With spissated residue and 260mg Anhydrous potassium carbonate, the 1-bromo-2-butyne of 0.1mL and the N of 5mL that all measures, dinethylformamide mixes.The mixture that generates was stirred under room temperature 2 hours.Reaction solution is diluted with ethyl acetate and water, and use ethyl acetate extraction.Organic layer water and saturated nacl aqueous solution are washed, and then through anhydrous magnesium sulfate drying.This liquid of concentrating under reduced pressure.Residue through using the silica gel column chromatography purification of 20-30% ethyl acetate/hexane, is prepared the oily mater of 290mg.With all oily mater and the N of 3mL of amount, the N-chloro-succinimide mixing of dinethylformamide and 120mg.The mixture that generates was stirred under room temperature 1 hour.Reaction solution is extracted with ethyl acetate and water.Organic layer water and saturated nacl aqueous solution are washed, and then through anhydrous magnesium sulfate drying.This liquid of concentrating under reduced pressure.Residue through using the silica gel column chromatography purification of 20-30% ethyl acetate/hexane, is prepared the title compound of 273mg.
1H-NMR(CDCl 3)δ：1.31(t，J＝7Hz，3H)1.82(t，J＝2Hz，3H)2.94(t，J＝8Hz，2H)4.21(t，J＝8Hz，2H)4.25(q，J＝7Hz，2H)4.78(s，2H)5.09(q，J＝2Hz，2H)7.19-7.24(m，1H)，7.26-7.33(m，4H)
(d) 4-[7-(2-butyne base)-3-ethoxy carbonyl methyl isophthalic acid-(2-phenylethyl)-2, the 6-dioxo -1,2,6,7-tetrahydrochysene purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
The mixture of piperazine-1-carboxylic acid tert-butyl ester that will contain [7-(2-butyne base)-8-chloro-1-(2-phenylethyl)-2,6-dioxo-1,2,6, the 7-tetrahydrochysene purine-3-yl] ethyl acetate of 273mg and 360mg in oil bath in 150 ℃ of heating 30 minutes.With the silica gel column chromatography purification of reaction solution, prepare the 320mg title compound by the ethyl acetate/hexane of use 20-30%.
1H-NMR(CDCl 3)δ：1.30(t，J＝7Hz，3H)1.49(s，9H)1.84(t，J＝2Hz，3H)2.93(t，J＝8Hz，2H)3.33(t，J＝5Hz，4H)3.57(t，J＝5Hz，4H)4.19(t，J＝8Hz，2H)4.25(q，J＝7Hz，2H)4.76(s，2H)4.86(q，J＝2Hz，2H)7.19(t，J＝7Hz，1H)7.25-7.34(m，4H)
(e) [the 7-tetrahydrochysene is fast for 7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6 Purine-3-yl] the ethyl acetate hydrochloride
4-[7-(2-butyne base)-3-ethoxy carbonyl methyl isophthalic acid-(the 2-phenylethyl)-2 that will contain 27mg, 6-dioxo-1,2,6,7-tetrahydrochysene purine-8-yl] mixture of piperazine-1-carboxylic acid tert-butyl ester and 0.25mL trifluoroacetic acid is in stirring at room 30 minutes.Concentrate this reaction solution, and, prepare the 17mg title compound the reversed-phase column chromatography method purification of residue by use 20-80% methanol (containing 0.1% concentrated hydrochloric acid).
1H-NMR(d6-DMSO)δ：1.22(t，J＝7Hz，3H)1.82(t，J＝2Hz，3H)2.80(t，J＝8Hz，2H)3.22-3.28(m，4H)3.46-3.51(m，4H)4.05(t，J＝8Hz，2H)4.17(q，J＝7Hz，2H)4.69(s，2H)4.96(q，J＝2Hz，2H)7.19-7.24(m，3H)7.30(t，J＝7Hz，2H)
Embodiment 417
[7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine -3-yl] the acetic acid hydrochloride
(f) 4-[7-(2-butyne base)-3-carboxymethyl-1-(2-phenylethyl)-2,6-dioxo-1,2,6, the 7-tetrahydrochysene is fast Purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
4-[7-(2-butyne base)-3-ethoxy carbonyl methyl isophthalic acid-(the 2-phenylethyl)-2 that will contain 190mg, 6-dioxo-1,2,6,7-tetrahydrochysene purine-8-yl] mixture of 1N-sodium hydrate aqueous solution of piperazine-1-carboxylic acid tert-butyl ester, 3mL ethanol and 0.5mL stirred 2 hours in 50 ℃ in oil bath.And the 1N aqueous hydrochloric acid solution of 0.55mL joined in the reaction solution, and then with ethyl acetate and water extraction.Organic layer water and saturated nacl aqueous solution are washed, and through anhydrous magnesium sulfate drying.This liquid of concentrating under reduced pressure, and ethyl acetate-hexane joined in this liquid be used for crystallization.Thereby prepare the 166mg title compound.
1H-NMR(CDCl 3)δ：1.49(s，9H)1.84(t，J＝2Hz，3H)2.93(t，J＝8Hz，2H)3.34(t，J＝5Hz，4H)3.58(t，J＝5Hz，4H)4.19(t，J＝8Hz，2H)4.82(s，2H)4.85(q，J＝2Hz，2H)7.19(t，J＝7Hz，1H)7.24-7.33(m，4H)
(g) [the 7-tetrahydrochysene is fast for 7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6 Purine-3-yl] the acetic acid hydrochloride
By the same procedure described in the embodiment 416-(e), use 4-[7-(2-butyne base)-3-carboxymethyl-1-(2-phenylethyl)-2 of 22mg, 6-dioxo-1,2,6,7-tetrahydrochysene purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester, prepare the 2.2mg title compound.
1H-NMR(d6-DMSO)δ：1.82(t，J＝2Hz，3H)2.80(t，J＝8Hz，2H)3.23-3.28(m，4H)3.46-3.53(m，4H)4.05(t，J＝8Hz，2H)4.59(s，2H)4.96(q，J＝2Hz，2H)7.19-7.25(m，3H)7.30(t，J＝7Hz，2H)
Embodiment 418
7-(2-butyne base)-3-[2-oxo-2-(pyrrolidine-1-yl) ethyl]-1-(2-phenethyl)-8-(piperazine-1- Base)-3,7-dihydro purine-2,6-diketone hydrochloride
4-[7-(2-butyne the base)-3-carboxymethyl-1-(2-phenylethyl)-2 that will contain 20mg, 6-dioxo-1,2,6,7-tetrahydrochysene purine-8-yl] N of piperazine-1-carboxylic acid tert-butyl ester, 8 μ L diethyl phosphorocyanidates, 10 μ L triethylamines, 20 μ L pyrrolidines and 0.3mL, the mixture of dinethylformamide left standstill under room temperature 3 days.Reaction solution is diluted with ethyl acetate and water, and use ethyl acetate extraction.Organic layer water and saturated nacl aqueous solution are washed, and concentrated then.The 0.5mL trifluoroacetic acid is joined in the residue, and the mixture that generates is incubated 30 minutes under room temperature.Concentrated reaction solution, and, prepare the 3.2mg title compound with the reversed-phase column chromatography method purification of residue by use 20-80% methanol (containing 0.1% concentrated hydrochloric acid).
1H-NMR (d6-DMSO) δ: 1.76-1.84 (m, and 5H) 1.95 (quintet, J=7Hz, 2H), 2.79 (t, J=8Hz, 2H) 3.22-3.34 (m, 6H) 3.45-3.52 (m, 4H) 3.55 (t, J=7Hz, 2H) 4.03 (t, J=8Hz, 2H) 4.68 (s, 2H) 4.96 (q, J=2Hz, 2H) 7.18-7.26 (m, 3H) 7.31 (t, J=8Hz, 2H)
Embodiment 419
2-[7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine -3-yl]-N-methylacetamide hydrochloride
By the same procedure described in the embodiment 418, use methylamine water solution, the synthetic title compound that obtains.
1H-NMR(d6-DMSO)δ：1.82(t，J＝2Hz，3H)2.61(d，J＝5Hz，3H)2.79(t，J＝8Hz，2H)3.20-3.28(m，4H)3.44-3.52(m，4H)4.03(t，J＝8Hz，2H)4.48(s，2H)4.96(q，J＝2Hz，2H)7.19-7.26(m，3H)7.31(t，J＝7Hz，2H)8.09(brd，J＝5Hz，1H)
Embodiment 420
2-[7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine -3-yl]-N-cyclopropyl acetamide hydrochloride
By the same procedure described in the embodiment 418, use cyclopropylamine, the synthetic title compound that obtains.
1H-NMR(d6-DMSO)δ：0.39-0.44(m，2H)0.60-0.66(m，2H)1.82(t，J＝2Hz，3H)2.60-2.68(m，1H)2.79(t，J＝8Hz，2H)3.20-3.30(m，4H)3.44-3.54(m，4H)4.03(t，J＝8Hz，2H)4.44(s，2H)4.96(q，J＝2Hz，2H)7.19-7.27(m，3H)7.31(t，J＝8Hz，2H)8.27(d，J＝4Hz，1H)
Embodiment 421
2-[7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine -3-yl]-N-phenyl acetamide hydrochloride
By the same procedure described in the embodiment 418, use aniline, the synthetic title compound that obtains.
1H-NMR(d6-DMSO)δ：1.83(t，J＝2Hz，3H)2.81(t，J＝8Hz，2H)3.20-3.30(m，4H)3.44-3.54(m，4H)4.05(t，J＝8Hz，2H)4.74(s，2H)，4.98(q，J＝2Hz，2H)7.06(t，J＝8Hz，1H)7.18-7.35(m，7H)7.56(d，J＝8Hz，2H)9.01(brs，2H)10.39(s，1H)
Embodiment 422
2-[7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine -3-yl]-N-(2-propynyl) acetamide hydrochloride
By the same procedure described in the embodiment 418, use propargyl amine, the synthetic title compound that obtains.
1H-NMR(d6-DMSO)δ：1.81(t，J＝3Hz)2.80(t，J＝8Hz，2H)3.18(t，J＝2Hz1H)，3.22-3.32(m，4H)3.44-3.54(m，4H)3.90(dd，J＝2Hz，5Hz，2H)4.03(t，J＝8Hz，2H)4.51(s，2H)4.96(q，J＝2Hz，2H)7.16-7.34(m，5H)8.66(t，J＝5Hz，1H)8.96(br.s，2H)
Embodiment 423
[the 7-tetrahydrochysene is fast for 7-(2-butyne base)-2,6-dioxo-1-(2-phenoxy group ethyl)-8-(piperazine-1-yl)-1,2,6 Purine-3-yl] the ethyl acetate hydrochloride
By the same procedure described in the embodiment 416, use 2 bromoethyl benzene base ether, the synthetic title compound that obtains.
1H-NMR(d6-DMSO)δ：1.20(t，J＝7Hz，3H)1.81(s，3H)3.22-3.28(m，4H)3.46-3.53(m，4H)4.06-4.19(m，4H)4.25(t，J＝6Hz，2H)4.69(s，2H)4.97(s，2H)6.88-6.96(m，3H)7.26(t，J＝7Hz，2H)8.96(brs，2H)
Embodiment 424
[1-methyl-2,6-dioxo-8-(piperazine-1-yl)-7-(2-ethenylphenyl)-1,2,6,7-tetrahydrochysene purine-3- Base] the ethyl acetate trifluoro-acetate
(a) [7-four for 1-(2,2-dimethyl propylene acyloxy methyl)-7-(2-formoxyl phenyl)-2,6-dioxo-1,2,6 Hydrogen purine-3-yl] methyl 2,2-dimethyl propylene acid esters
With 10.2g [3-(2; 2-dimethyl propylene acyloxy methyl)-2; 6-dioxo-2; 3; 6,7-tetrahydrochysene purine-1-yl] methyl 2, the 2-formoxyl phenylboric acid of 2-dimethyl propylene acid esters, 8.04g and 7.30g copper acetate (II) are suspended in the N of 50mL; in the dinethylformamide, and add the 4.34mL pyridine then.Mixture was stirred under room temperature 37 hours.Reaction solution is diluted with ethyl acetate, and wash with water.Organic layer through anhydrous magnesium sulfate drying, and is filtered.Concentrating under reduced pressure filtrate.With residue through the silica gel column chromatography purification.Thereby from part, prepare the 4.12g title compound with hexane-ethyl acetate (1: 2) eluting.
1H-NMR(CDCl 3)δ：1.16(s，9H)1.23(s，9H)5.95(s，2H)6.20(s，2H)7.46-7.48(m，1H)7.42-7.78(m，2H)7.75(s，1H)8.03-8.06(m，1H)9.92(s，1H)
(b) [8-chloro-1-(2,2-dimethyl propylene acyloxy methyl)-7-(2-formoxyl phenyl)-2,6-dioxo -1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2,2-dimethyl propylene acid esters
[1-(2,2-dimethyl propylene acyloxy methyl)-7-(2-formoxyl phenyl)-2,6-dioxo-1 with 2.50g; 2,6,7-tetrahydrochysene purine-3-yl] methyl 2; the N-chloro-succinimide of 2-dimethyl propylene acid esters and 896mg is dissolved in the N of 25mL, in the dinethylformamide.The mixture that generates was stirred under room temperature 8 hours.Reaction solution is diluted with ethyl acetate, and wash with water.Organic layer is also filtered through anhydrous magnesium sulfate drying.Concentrating under reduced pressure filtrate, and with residue through the silica gel column chromatography purification.Thereby from part, prepare the 2.0g title compound with hexane-ethyl acetate (2: 1) eluting.
1H-NMR(CDCl 3)δ：1.15(s，9H)1.24(s，9H)5.91(s，2H)6.14(s，2H)7.49-7.51(m，1H)7.81-7.83(m，2H)8.03-8.06(m，1H)9.92(s，1H)
(c) 4-[1, two (2,2-dimethyl propylene acyloxy the methyl)-7-(2-formoxyl phenyl)-2 of 3-, 6-dioxo -2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
With [8-chloro-1-(2,2-dimethyl-propionyloxy methyl)-7-(2-formoxyl phenyl)-2,6-dioxo-1,2,6,7-tetrahydrochysene purine-3-yl] methyl 2 of 2.0g, 2-dimethyl propylene acid esters mixes with piperazine-1-carboxylic acid tert-butyl ester of 2.15g.The mixture that generates was stirred 70 minutes down in 150 ℃.Reactant mixture is diluted with chloroform, and then by the silica gel column chromatography purification.Thereby from part, prepare the 1.94g title compound with hexane-ethyl acetate (1: 1) eluting.
(d) 4-[1, two (2,2-dimethyl propylene acyloxy methyl)-2 of 3-, 6-dioxo-7-(2-vinyl benzene Base)-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
3.52g Diethylaminoethyl triphenyl phosphonium is dissolved in the 20mL oxolane, and adds the 948mg potassium tert-butoxide then.The mixture that generates was stirred under room temperature 1 hour.The 4-[1 that will contain 1.94g, two (2,2-dimethyl propylene acyloxy the methyl)-7-(2-formoxyl phenyl)-2 of 3-; 6-dioxo-2; 3,6,7-tetrahydrochysene-1H-purine-8-yl] the 20mL tetrahydrofuran solution of piperazine-1-carboxylic acid tert-butyl ester joins in this reactant mixture under room temperature.Mixture was stirred under room temperature 3 hours 50 minutes again.Reaction solution is diluted with ethyl acetate, and wash with water then.Organic layer through anhydrous magnesium sulfate drying, and is filtered.Concentrating under reduced pressure filtrate.With residue through the silica gel column chromatography purification.Therefore from part, prepare the 704mg title compound with hexane-ethyl acetate (2: 1) eluting.
(e) 4-[1-(2,2-dimethyl propylene acyloxy methyl)-2,6-dioxo-7-(2-ethenylphenyl)-2,3,6,7- Tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
With the 4-[1 of 704mg, two (2,2-dimethyl propylene acyloxy methyl)-2 of 3-, 6-dioxo-7-(2-ethenylphenyl)-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the mixed solvent of 7mL oxolane and 14mL methanol, and adds the 51mg sodium hydride then.The mixture that generates was stirred under room temperature 17 minutes.Reaction solution is diluted with chloroform, and wash with saturated nacl aqueous solution.Organic layer through anhydrous magnesium sulfate drying, and is filtered.Concentrating under reduced pressure filtrate, and with residue through the silica gel column chromatography purification.Thereby from part, prepare the 510mg title compound with hexane-ethyl acetate (2: 3) eluting.
(f) 4-[1-(2,2-dimethyl propylene acyloxy methyl)-3-ethoxy carbonyl methyl-2,6-dioxo-7-(2- Ethenylphenyl)-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
With the 4-[1-(2,2-dimethyl propylene acyloxy methyl)-2 of 80mg, 6-dioxo-7-(2-ethenylphenyl)-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the N of 2mL, in the dinethylformamide, and add 19 μ L bromoacetates and 22mg potassium carbonate then.The mixture that generates was stirred under room temperature 14 hours.Reaction solution is diluted with ethyl acetate, and wash with water.Organic layer through anhydrous magnesium sulfate drying, and is filtered.Concentrating under reduced pressure filtrate prepares the 89mg title compound.
(g) 4-[3-ethoxy carbonyl methyl-2,6-dioxo-7-(2-ethenylphenyl)-2,3,6,7-tetrahydrochysene-1H- Purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
4-[1-(2 with 89mg, 2-dimethyl propylene acyloxy methyl)-3-ethoxy carbonyl methyl-2,6-dioxo-7-(2-ethenylphenyl)-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the mixed solvent that contains 1mL oxolane and 2mL methanol, and adds the 7mg sodium hydride then.The mixture that generates was stirred under room temperature 35 hours.Reaction solution is diluted with ethyl acetate, and wash with water.Organic layer through anhydrous magnesium sulfate drying, and is filtered.Concentrating under reduced pressure filtrate.With residue through the silica gel column chromatography purification.Thereby from part, prepare the 60mg title compound with hexane-ethyl acetate (1: 2) eluting.
(h) 4-[3-ethoxy carbonyl methyl isophthalic acid-methyl-2,6-dioxo-7-(2-ethenylphenyl)-2,3,6,7-four Hydrogen-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester
With the 4-[3-ethoxy carbonyl methyl-2 of 60mg, 6-dioxo-7-(2-ethenylphenyl)-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the N of 2mL, in the dinethylformamide, and adds 17 μ L iodomethane and 17mg potassium carbonate then.The mixture that generates was stirred under room temperature 13 hours.Reaction solution is diluted with ethyl acetate, and wash with water.Organic layer through anhydrous magnesium sulfate drying, and is filtered.Concentrating under reduced pressure filtrate prepares the 48mg title compound.
(i) [1-methyl-2,6-dioxo-8-(piperazine-1-yl)-7-(2-ethenylphenyl)-1,2,6,7-tetrahydrochysene purine -3-yl] the ethyl acetate trifluoro-acetate
With 4-[3-ethoxy carbonyl methyl isophthalic acid-methyl-2 of 8mg, 6-dioxo-7-(2-ethenylphenyl)-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the trifluoroacetic acid, and concentrated then this solution.Residue by the reversed phase high-performance liquid chromatography purification, is prepared the 2.68mg title compound.
MS?m/e(ESI)439(MH +-CF 3COOH)
Embodiment 425
[1-methyl-2,6-dioxo-8-(piperazine-1-yl)-7-(2-ethenylphenyl)-1,2,6,7-tetrahydrochysene purine-3- Base] the acetic acid trifluoro-acetate
With 4-[3-ethoxy carbonyl methyl isophthalic acid-methyl-2 of 40mg, 6-dioxo-7-(2-ethenylphenyl)-2,3,6,7-tetrahydrochysene-1H-purine-8-yl] piperazine-1-carboxylic acid tert-butyl ester is dissolved in the 4mL oxolane, and adds the 2N sodium hydroxide of 1mL then.The mixture that generates was stirred 4 hours down in 90 ℃.The concentrating under reduced pressure reaction solution, and handle by azeotropic distillation with toluene then.Residue is dissolved in the trifluoroacetic acid, and concentrates this solution.Residue by the reversed phase high-performance liquid chromatography purification, is prepared the 29.5mg title compound.
MS?m/e(ESI)411(MH +-CF 3COOH)
The following formula representative can be synthesized the chemical compound that obtains by above-mentioned common synthetic method and with the same procedure described in above-mentioned preparation embodiment and the embodiment really.
Preparation embodiment 1 (a)
Figure A0382539401691
Preparation embodiment 1 (b)
Preparation embodiment 1 (c)
Preparation embodiment 1 (d)
Preparation embodiment 2 (a)
Preparation embodiment 2 (b)
Preparation embodiment 2 (c)
Figure A0382539401704
Preparation embodiment 2 (d)
Embodiment 1 (a)
Figure A0382539401706
Embodiment 1 (b)
Figure A0382539401711
Embodiment 1 (c)
Figure A0382539401712
Embodiment 1 (d)
Figure A0382539401713
Embodiment 1 (e)
Figure A0382539401714
Embodiment 1 (f)
Embodiment 1 (g)-1
Embodiment 1 (g)-2
Embodiment 1 (h)
Embodiment 2
Figure A0382539401724
Embodiment 3 (a)
Embodiment 3 (b)
Embodiment 3 (c)
Embodiment 3 (d)
Embodiment 3 (e)
Embodiment 3 (f)
Embodiment 4 (a)
Embodiment 4 (b)
Figure A0382539401742
Embodiment 4 (c)
Figure A0382539401743
Embodiment 4 (d)
Embodiment 5
Embodiment 6
Figure A0382539401746
Embodiment 7
Figure A0382539401751
Embodiment 8
Embodiment 9
Embodiment 10
Figure A0382539401754
Embodiment 11 (a)-1
Embodiment 11 (a)-2
Figure A0382539401756
Embodiment 11 (b)
Figure A0382539401761
Embodiment 12
Embodiment 13
Embodiment 14
Figure A0382539401764
Embodiment 15
Embodiment 16
Figure A0382539401766
Embodiment 17
Figure A0382539401771
Embodiment 18
Embodiment 19
Embodiment 20
Embodiment 21
Embodiment 22
Figure A0382539401776
Embodiment 23
Figure A0382539401781
Embodiment 24
Figure A0382539401782
Embodiment 25
Figure A0382539401783
Embodiment 26
Embodiment 27
Figure A0382539401785
Embodiment 28
Embodiment 29
Embodiment 30
Figure A0382539401792
Embodiment 31
Figure A0382539401793
Embodiment 32
Embodiment 33
Figure A0382539401795
Embodiment 34
Embodiment 35
Figure A0382539401801
Embodiment 36
Embodiment 37
Embodiment 38
Figure A0382539401804
Embodiment 39
Figure A0382539401805
Embodiment 40
Figure A0382539401806
Embodiment 41
Figure A0382539401811
Embodiment 42
Figure A0382539401812
Embodiment 43
Embodiment 44
Figure A0382539401814
Embodiment 45
Figure A0382539401815
Embodiment 46
Embodiment 47
Figure A0382539401821
Embodiment 48
Figure A0382539401822
Embodiment 49
Figure A0382539401823
Embodiment 50
Embodiment 51
Embodiment 52
Embodiment 53
Figure A0382539401831
Embodiment 54
Figure A0382539401832
Embodiment 55
Figure A0382539401833
Embodiment 56
Embodiment 57
Figure A0382539401835
Embodiment 58
Embodiment 59
Embodiment 60
Figure A0382539401843
Embodiment 61
Embodiment 62
Figure A0382539401845
Embodiment 63
Figure A0382539401846
Embodiment 64
Embodiment 65
Embodiment 66
Embodiment 67
Figure A0382539401854
Embodiment 68
Figure A0382539401855
Embodiment 69
Figure A0382539401856
Embodiment 70
Embodiment 71
Embodiment 72
Figure A0382539401863
Embodiment 73
Figure A0382539401864
Embodiment 74
Embodiment 75
Figure A0382539401866
Embodiment 76
Figure A0382539401867
Embodiment 77
Figure A0382539401871
Embodiment 78
Embodiment 79
Figure A0382539401873
Embodiment 80
Figure A0382539401874
Embodiment 81
Embodiment 82
Embodiment 83 (a)
Figure A0382539401881
Embodiment 83 (b)
Figure A0382539401882
Embodiment 84
Figure A0382539401883
Embodiment 85
Figure A0382539401884
Embodiment 86 (a)
Embodiment 86 (b)
Embodiment 86 (c)
Embodiment 86 (d)
Embodiment 86 (e)
Figure A0382539401893
Embodiment 87
Embodiment 88
Figure A0382539401895
Embodiment 89
Figure A0382539401896
Embodiment 90
Figure A0382539401901
Embodiment 91
Figure A0382539401902
Embodiment 92
Figure A0382539401903
Embodiment 93
Embodiment 94
Embodiment 95 (a)
Embodiment 95 (b)
Embodiment 96 (a)
Figure A0382539401912
Embodiment 96 (b)
Figure A0382539401913
Embodiment 96 (c)
Figure A0382539401914
Embodiment 97
Figure A0382539401915
Embodiment 98
Figure A0382539401916
Embodiment 99 (a)
Figure A0382539401917
Embodiment 99 (b)
Embodiment 100 (a)
Figure A0382539401922
Embodiment 100 (b)
Embodiment 101
Embodiment 102
Figure A0382539401925
Embodiment 103 (a)
Embodiment 103 (b)
Figure A0382539401927
Embodiment 104
Embodiment 105
Figure A0382539401932
Embodiment 106 (a)
Embodiment 106 (b)
Embodiment 107
Figure A0382539401935
Embodiment 108
Embodiment 109 (a)
Figure A0382539401937
Embodiment 109 (b)
Figure A0382539401941
Embodiment 109 (c)
Figure A0382539401942
Embodiment 110
Figure A0382539401943
Embodiment 111
Embodiment 112
Figure A0382539401945
Embodiment 113
Embodiment 114
Embodiment 115 (a)
Figure A0382539401952
Embodiment 115 (b)
Embodiment 115 (c)
Figure A0382539401954
Embodiment 115 (d)
Figure A0382539401955
Embodiment 115 (e)
Figure A0382539401956
Embodiment 115 (f)
Embodiment 115 (g)
Embodiment 115 (h)
Figure A0382539401962
Embodiment 115 (i)
Embodiment 116 (a)
Figure A0382539401964
Embodiment 116 (b)
Embodiment 116 (c)
Embodiment 116 (d)
Embodiment 116 (e)
Figure A0382539401971
Embodiment 117
Figure A0382539401972
Embodiment 118 (a)
Embodiment 118 (b)
Embodiment 119 (a)
Figure A0382539401975
Embodiment 119 (b)
Figure A0382539401981
Embodiment 119 (c)
Embodiment 119 (d)
Figure A0382539401983
Embodiment 119 (e)
Figure A0382539401984
Embodiment 120 (a)
Embodiment 120 (b)
Embodiment 120 (c)
Embodiment 121
Figure A0382539401992
Embodiment 122
Figure A0382539401993
Embodiment 123
Embodiment 124
Figure A0382539401995
Embodiment 125
Figure A0382539401996
Embodiment 126
Embodiment 127
Embodiment 128
Embodiment 129
Embodiment 130
Figure A0382539402005
Embodiment 131
Figure A0382539402006
Embodiment 132
Embodiment 133
Figure A0382539402011
Embodiment 134
Figure A0382539402012
Embodiment 135
Figure A0382539402013
Embodiment 136
Figure A0382539402014
Embodiment 137
Figure A0382539402015
Embodiment 138
Figure A0382539402016
Embodiment 139
Figure A0382539402021
Embodiment 140
Figure A0382539402022
Embodiment 141
Embodiment 142
Embodiment 143
Embodiment 144
Figure A0382539402026
Embodiment 145
Embodiment 146
Figure A0382539402032
Embodiment 147
Embodiment 148
Figure A0382539402034
Embodiment 149
Embodiment 150
Figure A0382539402036
Embodiment 151
Embodiment 152
Figure A0382539402042
Embodiment 153
Embodiment 154
Figure A0382539402044
Embodiment 155
Figure A0382539402045
Embodiment 156
Figure A0382539402046
Embodiment 157
Embodiment 158
Embodiment 159
Figure A0382539402053
Embodiment 160
Figure A0382539402054
Embodiment 161
Figure A0382539402055
Embodiment 162
Embodiment 163
Embodiment 164
Embodiment 165
Figure A0382539402063
Embodiment 166
Figure A0382539402064
Embodiment 167
Figure A0382539402065
Embodiment 168
Figure A0382539402066
Embodiment 169
Figure A0382539402071
Embodiment 170
Figure A0382539402072
Embodiment 171
Figure A0382539402073
Embodiment 172
Embodiment 173
Embodiment 174
Embodiment 175
Figure A0382539402081
Embodiment 176
Embodiment 177
Embodiment 178
Embodiment 179
Embodiment 180
Figure A0382539402086
Embodiment 181
Figure A0382539402091
Embodiment 182
Embodiment 183
Embodiment 184
Embodiment 185
Embodiment 186
Embodiment 187
Figure A0382539402101
Embodiment 188
Embodiment 189
Figure A0382539402103
Embodiment 190
Figure A0382539402104
Embodiment 191
Figure A0382539402105
Embodiment 192
Embodiment 193
Embodiment 194
Embodiment 195
Embodiment 196
Embodiment 197
Figure A0382539402122
Embodiment 198
Figure A0382539402123
Embodiment 199
Figure A0382539402124
Embodiment 200,201
Embodiment 202
Embodiment 203
Figure A0382539402133
Embodiment 204
Embodiment 205
Figure A0382539402141
Embodiment 206
Embodiment 207
Embodiment 208
Embodiment 209
Figure A0382539402151
Embodiment 210
Figure A0382539402152
Embodiment 211
Figure A0382539402153
Embodiment 212
Figure A0382539402154
Embodiment 213
Embodiment 214
Figure A0382539402162
Embodiment 215
Figure A0382539402163
Embodiment 216
Embodiment 217
Figure A0382539402165
Embodiment 218
Figure A0382539402166
Embodiment 219
Figure A0382539402171
Embodiment 220
Figure A0382539402172
Embodiment 221
Embodiment 222
Embodiment 223 (a)
Figure A0382539402175
Embodiment 223 (b)
Figure A0382539402176
Embodiment 224
Figure A0382539402181
Embodiment 225
Embodiment 226
Figure A0382539402183
Embodiment 227
Embodiment 228
Embodiment 229 (a)
Embodiment 229 (b)
Embodiment 230
Figure A0382539402192
Embodiment 231
Figure A0382539402193
Embodiment 232
Embodiment 233
Figure A0382539402195
Embodiment 234
Figure A0382539402201
Embodiment 235 (a)
Figure A0382539402202
Embodiment 235 (b)
Embodiment 236
Figure A0382539402204
Embodiment 237
Embodiment 238 (a)
Figure A0382539402212
Embodiment 238 (b)
Embodiment 239
Embodiment 240 (a)
Figure A0382539402215
Embodiment 240 (b)
Figure A0382539402221
Embodiment 240 (c)
Figure A0382539402222
Embodiment 241
Embodiment 242 (a)
Figure A0382539402224
Embodiment 242 (b)
Figure A0382539402225
Embodiment 242 (c)
Embodiment 242 (d)
Figure A0382539402227
Embodiment 242 (e)
Embodiment 242 (f)
Figure A0382539402232
Embodiment 242 (g)
Embodiment 243
Embodiment 244 (a)
Embodiment 244 (b)
Embodiment 245
Embodiment 246 (a)
Figure A0382539402242
Embodiment 246 (b)
Figure A0382539402243
Embodiment 247
Figure A0382539402244
Embodiment 248 (a)
Figure A0382539402245
Embodiment 248 (b)
Figure A0382539402246
Embodiment 249
Figure A0382539402251
Embodiment 250
Figure A0382539402252
Embodiment 251
Embodiment 252
Embodiment 253
Embodiment 254 (a)
Figure A0382539402256
Embodiment 254 (b)
Figure A0382539402261
Embodiment 254 (c)
Embodiment 254 (d)
Figure A0382539402263
Embodiment 255
Embodiment 256
Figure A0382539402265
Embodiment 257
Embodiment 258 (a)
Figure A0382539402271
Embodiment 258 (b)
Embodiment 259
Figure A0382539402273
Embodiment 260
Figure A0382539402274
Embodiment 261
Figure A0382539402275
Embodiment 262
Figure A0382539402276
Embodiment 263
Embodiment 264
Figure A0382539402281
Embodiment 265
Figure A0382539402282
Embodiment 266
Figure A0382539402283
Embodiment 267
Figure A0382539402284
Embodiment 268
Embodiment 269
Figure A0382539402286
Embodiment 270
Figure A0382539402287
Embodiment 271
Embodiment 272
Figure A0382539402292
Embodiment 273
Embodiment 274
Figure A0382539402294
Embodiment 275
Figure A0382539402295
Embodiment 276
Embodiment 277
Figure A0382539402297
Embodiment 278
Figure A0382539402301
Embodiment 279
Embodiment 280
Figure A0382539402303
Embodiment 281
Figure A0382539402304
Embodiment 282
Figure A0382539402305
Embodiment 283
Embodiment 284
Figure A0382539402307
Embodiment 285
Embodiment 286
Embodiment 287
Embodiment 288
Embodiment 289
Embodiment 290
Embodiment 291
Figure A0382539402317
Embodiment 292
Figure A0382539402321
Embodiment 293
Embodiment 294
Figure A0382539402323
Embodiment 295
Figure A0382539402324
Embodiment 296
Embodiment 297
Embodiment 298
Figure A0382539402331
Embodiment 299
Figure A0382539402332
Embodiment 300
Embodiment 301
Embodiment 302
Embodiment 303
Embodiment 304
Embodiment 305
Figure A0382539402341
Embodiment 306
Figure A0382539402342
Embodiment 307
Embodiment 308 (a)
Figure A0382539402344
Embodiment 308 (b)
Embodiment 309 (a)
Embodiment 309 (b)
Embodiment 310
Embodiment 311
Figure A0382539402352
Embodiment 312
Figure A0382539402353
Embodiment 313
Figure A0382539402354
Embodiment 314
Figure A0382539402355
Embodiment 315
Figure A0382539402356
Embodiment 316
Embodiment 317
Figure A0382539402361
Embodiment 318
Embodiment 319
Embodiment 320
Figure A0382539402364
Embodiment 321
Embodiment 322
Figure A0382539402366
Embodiment 323
Embodiment 324
Embodiment 325 (a)
Figure A0382539402372
Embodiment 325 (b)
Figure A0382539402373
Embodiment 326 (a)
Figure A0382539402374
Embodiment 326 (b)
Embodiment 326 (c)
Figure A0382539402376
Embodiment 327 (a)
Embodiment 327 (b)
Embodiment 327 (c)
Figure A0382539402383
Embodiment 327 (d)
Figure A0382539402384
Embodiment 328
Embodiment 329
Figure A0382539402391
Embodiment 330
Embodiment 331 (a)
Figure A0382539402393
Embodiment 331 (b)
Embodiment 332 (a)
Figure A0382539402395
Embodiment 332 (b)
Figure A0382539402396
Embodiment 332 (c)
Embodiment 332 (d)
Embodiment 332 (e)
Figure A0382539402403
Embodiment 333
Embodiment 334 (a)
Embodiment 334 (b)
Embodiment 334 (c)
Embodiment 334 (d)
Figure A0382539402412
Embodiment 334 (e)
Embodiment 334 (f)
Figure A0382539402414
Embodiment 335 (a)
Embodiment 335 (b)
Figure A0382539402416
Embodiment 335 (c)
Figure A0382539402421
Embodiment 335 (d)
Figure A0382539402422
Embodiment 336 (a)
Embodiment 336 (b)
Embodiment 336 (c)
Embodiment 336 (d)
Figure A0382539402426
Embodiment 337 (a)
Embodiment 337 (b)
Figure A0382539402431
Embodiment 337 (c)
Embodiment 337 (d)
Embodiment 337 (e)
Figure A0382539402434
Embodiment 337 (f)
Embodiment 337 (g)
Figure A0382539402436
Embodiment 337 (h)
Figure A0382539402441
Embodiment 338 (a)
Embodiment 338 (b)
Figure A0382539402443
Embodiment 338 (c)
Figure A0382539402444
Embodiment 338 (d)
Figure A0382539402445
Embodiment 338 (e)
Embodiment 338 (f)
Embodiment 338 (g)
Figure A0382539402451
Embodiment 338 (h)
Embodiment 338 (i)
Embodiment 338 (j)
Figure A0382539402454
Embodiment 338 (k)
Figure A0382539402455
Embodiment 338 (l)
Embodiment 339 (a)
Embodiment 339 (b)
Figure A0382539402462
Embodiment 340
Figure A0382539402463
Embodiment 341
Figure A0382539402464
Embodiment 342
Embodiment 343 (a)
Figure A0382539402466
Embodiment 343 (b)
Figure A0382539402467
Embodiment 343 (c)
Figure A0382539402471
Embodiment 343 (d)
Figure A0382539402472
Embodiment 343 (e)
Figure A0382539402473
Embodiment 343 (f)
Embodiment 343 (g)
Embodiment 343 (h)
Figure A0382539402476
Embodiment 344
Figure A0382539402481
Embodiment 345
Embodiment 346
Embodiment 347
Figure A0382539402484
Embodiment 348
Figure A0382539402485
Embodiment 349 (a)-1
Figure A0382539402486
Embodiment 349 (a)-2
Figure A0382539402491
Embodiment 349 (b)
Embodiment 349 (c)
Embodiment 350
Embodiment 351
Figure A0382539402495
Embodiment 352 (a)
Figure A0382539402501
Embodiment 352 (b)
Embodiment 352 (c)
Embodiment 352 (d)
Figure A0382539402504
Embodiment 352 (e)
Embodiment 353 (a)
Embodiment 353 (b)
Figure A0382539402511
Embodiment 354 (a)
Embodiment 354 (b)
Embodiment 355
Figure A0382539402514
Embodiment 356
Figure A0382539402515
Embodiment 357
Figure A0382539402516
Embodiment 358
Figure A0382539402521
Embodiment 359
Embodiment 360
Figure A0382539402523
Embodiment 361
Embodiment 362.
Figure A0382539402525
Embodiment 363
Figure A0382539402526
Embodiment 364
Embodiment 365
Embodiment 366
Figure A0382539402533
Embodiment 367
Figure A0382539402534
Embodiment 368
Embodiment 369 (a)
Embodiment 369 (b)
Embodiment 370 (a)
Embodiment 370 (b)
Figure A0382539402543
Embodiment 371
Figure A0382539402544
Embodiment 372 (a)
Embodiment 372 (b)
Figure A0382539402546
Embodiment 372 (c)
Embodiment 372 (d)
Embodiment 373 (a)
Figure A0382539402553
Embodiment 373 (b)
Figure A0382539402554
Embodiment 373 (c)
Figure A0382539402555
Embodiment 373 (d)
Embodiment 373 (e)
Embodiment 373 (f)
Figure A0382539402562
Embodiment 373 (g)
Embodiment 374
Figure A0382539402564
Embodiment 375
Figure A0382539402565
Embodiment 376
Figure A0382539402571
Embodiment 377
Embodiment 378
Figure A0382539402573
Embodiment 379
Figure A0382539402574
Embodiment 380
Figure A0382539402575
Embodiment 381
Figure A0382539402581
Embodiment 382
Embodiment 383
Figure A0382539402583
Embodiment 384 (a)
Embodiment 384 (b)
Embodiment 384 (c)
Figure A0382539402586
Embodiment 384 (d)
Embodiment 385 (a)
Figure A0382539402592
Embodiment 385 (b)
Embodiment 385 (c)
Figure A0382539402594
Embodiment 385 (d)
Figure A0382539402595
Embodiment 385 (e)
Embodiment 385 (f)
Embodiment 385 (g)
Figure A0382539402603
Embodiment 385 (h)
Figure A0382539402604
Embodiment 386
Embodiment 387
Embodiment 388
Embodiment 389
Embodiment 390 (a)
Embodiment 390 (b)
Figure A0382539402615
Embodiment 391 (a)
Embodiment 391 (b)
Embodiment 392
Figure A0382539402623
Embodiment 393
Figure A0382539402624
Embodiment 394
Figure A0382539402625
Embodiment 395 (a)
Figure A0382539402631
Embodiment 395 (b)
Figure A0382539402632
Embodiment 395 (c)
Figure A0382539402633
Embodiment 395 (d)
Embodiment 395 (e)
Figure A0382539402641
Embodiment 395 (f)
Embodiment 395 (g)
Figure A0382539402643
Embodiment 396 (a)
Figure A0382539402644
Embodiment 396 (b)
Embodiment 396 (c)
Embodiment 396 (d)
Embodiment 397
Figure A0382539402653
Embodiment 398
Figure A0382539402654
Embodiment 399
Embodiment 400
Embodiment 401
Figure A0382539402662
Embodiment 402
Embodiment 403
Embodiment 404
Figure A0382539402665
Embodiment 405
Figure A0382539402671
Embodiment 406
Figure A0382539402672
Embodiment 407
Figure A0382539402673
Embodiment 408
Embodiment 409
Figure A0382539402675
Embodiment 410
Figure A0382539402681
Embodiment 411 (a)
Embodiment 411 (b)
Figure A0382539402683
Embodiment 411 (c)
Embodiment 412
Embodiment 413
Figure A0382539402691
Embodiment 414 (a)
Embodiment 414 (b)
Figure A0382539402693
Embodiment 415
Figure A0382539402694
Embodiment 416 (a)
Embodiment 416 (b)
Embodiment 416 (c)
Embodiment 416 (d)
Figure A0382539402703
Embodiment 416 (e)
Embodiment 417 (a)
Embodiment 417 (b)
Figure A0382539402711
Embodiment 418
Embodiment 419
Embodiment 420
Figure A0382539402714
Embodiment 421
Figure A0382539402715
Embodiment 422
Figure A0382539402721
Embodiment 423
Figure A0382539402722
Embodiment 424 (a)
Figure A0382539402723
Embodiment 424 (b)
Figure A0382539402724
Embodiment 424 (c)
Embodiment 424 (d)
Figure A0382539402732
Embodiment 424 (e)
Figure A0382539402733
Embodiment 424 (f)
Embodiment 424 (g)
Figure A0382539402741
Embodiment 424 (h)
Figure A0382539402742
Embodiment 424 (i)
Embodiment 425
[experimental example 1]
The chemical compound of formula (I) representative suppresses the active test of DPPIV
To be dissolved in reaction buffer (among the 50mMTris-HCl (pH 7.4)/0.1%BSA) with the ultimate density of 10m μ/ml from the DPPIV of Ren sus domestica.110 μ l of this enzymatic solution are partly joined in the reaction system, and add 15 μ l reagent then.Reaction solution at room temperature is incubated 20 minutes.To contain 2mMGly-Pro-joins in this reaction solution (ultimate density is 0.33mM) with the beginning enzyme reaction 25 μ l solution of p-nitroanilide (anilide).Response time is 20 minutes.The 1N phosphate solution that adds 25 μ l is to stop this reaction.Absorbance at 405nm place working sample.Determine inhibition degree, and calculate IC based on absorbance to enzyme reaction 50
[table 1]
Embodiment number ??IC 50(nM) Embodiment number ??IC 50(nM)
Embodiment 1 ??287 Embodiment 4 ??211
Embodiment 7 ??401 Embodiment 9 ??141
Embodiment 12 ??183 Embodiment 13 ??125
Embodiment 16 ??272 Embodiment 20 ??152
Embodiment 22 ??17 Embodiment 29 ??310
Embodiment 53 ??46.9 Embodiment 64 ??126
Embodiment 73 ??33.4 Embodiment 76 ??86.5
Embodiment 79 ??35.7 Embodiment 82 ??161
Embodiment 83 ??27.4 Embodiment 86 ??4.08
Embodiment 88 ??2.89 Embodiment 98 ??9.69
Embodiment 109 ??1480 Embodiment 115 ??185
Embodiment 119 ??154 Embodiment 120 ??116
Embodiment 122 ??15.3 Embodiment 129 ??115
Embodiment 142 ??68.5 Embodiment 146 ??81.7
Embodiment 159 ??37.7 Embodiment 229 ??8.97
Embodiment 230 ??0.890 Embodiment 234 ??1.74
Embodiment 235 ??1.44 Embodiment 238 ??1.19
Embodiment 243 ??2.15 Embodiment 248 ??6.40
Embodiment 266 ??1.15 Embodiment 267 ??7.22
Embodiment 297 ??6.22 Embodiment 311 ??77.5
Embodiment 341 ??7.32 Embodiment 353 ??283
Embodiment 354 ??285 Embodiment 355 ??147
Embodiment 357 ??323 Embodiment 358 ??357
Embodiment 359 ??353 Embodiment 361 ??0.654
Embodiment 364 ??9.48 Embodiment 367 ??4.56
Embodiment 377 ??8.77 Embodiment 378 ??9.52
Embodiment 382 ??6.97 Embodiment 383 ??7.18
Embodiment 393 ??1.2 Embodiment 394 ??2.16
Embodiment 396 ??197 Embodiment 398 ??237
Embodiment 400 ??183 Embodiment 402 ??354
Embodiment 403 ??266 Embodiment 404 ??276
Embodiment 405 ??359 Embodiment 407 ??275
Embodiment 408 ??340 Embodiment 409 ??222
Embodiment 410 ??64.9 Embodiment 413 ??1.95
Embodiment 415 ??1.81 Embodiment 416 ??4.02
Embodiment 417 ??0.864 Embodiment 418 ??1.14
Embodiment 419 ??1.55 Embodiment 420 ??1.70
Embodiment 421 ??3.37 Embodiment 422 ??0.472
[experimental example 2]
GLP-1 concentration in the rat that metformin, buformin and phenformin lack DPPIV- Influence
The male Fisher rat that animal: DPPIV-lacks is (available from Charles River Japan, Inc.)
Method:
[preparation of test compounds and give]
Each test compounds is suspended in 0.5% methocel solution with the dosage shown in the table 2, and gives with the volume per os of 5mL/kg then.The vehicle Control group is the solution that gives 0.5% methylcellulose with the volume per os of 5mL/kg.
[blood collection and GLP-1 test]
With the rat of not anesthesia with razor (razor blade) before test compounds or 0.5% methocel solution are severed and given in tail vein place gently and giving blood-letting immediately in 1,3 and 5 hour afterwards.The capillary tube that uses heparinization is by gathering the blood of 250 μ L in the rat and being transferred to centrifuge tube.Use ActiveGLP-1ELISA test kit (Linco) to measure the GLP-1 concentration of the supernatant that is obtained by centrifuging (in 4 ℃ with centrifugal 2 minutes of 10000g).
The result:
The result represents with " mean+/-standard error ".Each value of evaluation and test by Dunnett compares, and is as shown in table 2.
[table 2]
Test compounds Dosage (mg/kg) Each time point behind the oral administration (hour) GLP-1 concentration (%ofPre)
??0 ??1 ??3 ??5
Vehicle Control ??100±0.0 ??87.2±4.8 ??100.4±7.8 ??110.0±6.8
Metformin ??30 ??100±0.0 ??99.9±3.7 ??106.6±5.0 ??116.3±2.7
Metformin ??100 ??100±0.0 ??111.6±7.9 ??116.3±8.2 ??150.6±7.2
Metformin ??300 ??100±0.0 ??140.0±11.5 ??199.3±32.4 ??227.1±35.5 *
Buformin ??30 ??100±0.0 ??118.7±9.3 ??122.7±7.1 ??114.6±4.4
Buformin ??100 ??100±0.0 ??163.6±19.6 * ??171.2±9.1 ??195.8±-36.6 *
Phenformin ??30 ??100±0.0 ??125.3±10.7 ??120.0±7.2 ??126.7±10.7
Phenformin ??100 ??100±0.0 ??316.9±26.4 *** ??330.7±112.4 * ??236.5±20.5 *
*: P＜0.05vs vehicle Control group
* *: P＜0.001vs vehicle Control group
The group that gives the rat that the DPPIV-of metformin lacks with 300mg/kg dosage obviously rises in the concentration of 5 hours active GLP-1 in blood plasma after the administration.The group that gives the rat that the DPPIV-of buformin lacks with 100mg/kg dosage obviously rises in the concentration of 1 and 5 hour active GLP-1 in blood plasma after the administration.And the group that gives the rat that the DPPIV-of phenformin lacks with 100mg/kg dosage obviously rises in the concentration of 1,3 and 5 hour active GLP-1 in blood plasma after the administration.
[experimental example 3]
Metformin of Shi Yonging and DPPIV inhibitor (valine pyrrolidine (Val-Pyr)) exist individually or simultaneously In the normal rat to the influence of GLP-1 concentration
The complete normal male Fisher rat of animal: DPPIV-is (available from CLEA Japan, Inc.)
Method:
[preparation of test compounds and give]
Each test compounds is suspended in 0.5% methocel solution with the dosage shown in the table 3, and gives with the volume per os of 5mL/kg then.The vehicle Control group is the solution that gives 0.5% methylcellulose with the volume per os of 5mL/kg.
[blood collection and GLP-1 test]
With the rat of not anesthesia with razor before test compounds or 0.5% methocel solution are severed and given in tail vein place gently and giving blood-letting immediately in 1,3 and 5 hour afterwards.The capillary tube that uses heparinization is by gathering the blood of 250 μ L in the rat and being transferred to centrifuge tube.Use Active GLP-1ELISA test kit (Linco) to measure the GLP-1 concentration of the supernatant that is obtained by centrifuging (in 4 ℃ with centrifugal 2 minutes of 10000g).
The result:
The result represents with " mean+/-standard error ".Each value of evaluation and test by Dunnett compares, and is as shown in table 3.
[table 3]
Test compounds Dosage (mg/kg) Each time point behind the oral administration (hour) GLP-1 concentration (%ofPre)
??0 ??1 ??3 ??5
Vehicle Control ??100±0.0 ??112±15 ??125±21 ??84±10
Metformin ??300 ??100±0.0 ??117±9 ??149±24 ??94±10
??Val-Pyr ??30 ??100±0.0 ??127±6 ??136±20 ??91±2
Metformin+Val-Pyr ??300 ??+ ??30 ??100±0.0 ??162±8 *** ??215±19 * ??177±15 ***
*: P＜0.05vs vehicle Control group
* *: P＜0.001vs vehicle Control group
When giving metformin or DPPIV inhibitor separately, the concentration of active GLP-1 does not increase.Yet, giving at the same time in the group of metformin and DPPIV inhibitor, the concentration of 1,3 and 5 hour active GLP-1 obviously rises after the administration.This result shows that the rising of active GLP-1 concentration is owing to increase the secretion of GLP-1 by metformin, and suppresses the decomposition of GLP-1 by the DPPIV inhibitor.
[experimental example 4]
Individually or simultaneously metformin of Shi Yonging and DPPIV inhibitor (embodiment 82,119,120,122, 229 and 267) in normal rat to the influence of GLP-1 concentration
The complete normal male Fisher rat of animal: DPPIV-is (available from CLEA Japan, Inc.)
Method:
[preparation of test compounds and give]
Each test compounds is suspended in 0.5% methocel solution with the dosage of table shown in the 4-6, and gives with the volume per os of 5mL/kg then.The vehicle Control group is the solution that gives 0.5% methylcellulose with the volume per os of 5mL/kg.
[blood collection and GLP-1 test]
With the rat of not anesthesia with razor before test compounds or 0.5% methocel solution are severed and given in tail vein place gently and giving blood-letting immediately in back 3 hours.The capillary tube that uses heparinization is by gathering the blood of 250 μ L in the rat and being transferred to centrifuge tube.Use Active GLP-1ELISA test kit (Linco) to measure the GLP-1 concentration of the supernatant that is obtained by centrifuging (in 4 ℃ with centrifugal 2 minutes of 10000g).
The result:
The result represents with " mean+/-standard error ".Each value of evaluation also compares by the Dunnett test, as showing as shown in the 4-6.
[table 4]
Test compounds Dosage (mg/kg) 3 hours GLP-1 concentration (%ofPre) behind the oral administration
Vehicle Control ??98.8±2.9
Embodiment 119 ??10 ??98.9±2.2
Embodiment 122 ??10 ??108.2±6.6
Metformin ??300 ??118.1±7.5
Metformin+embodiment 119 ??300+10 ??162.5±7.4 ***
Metformin+embodiment 122 ??300+10 ??168.1±13.1 ***
* *: P＜0.001vs vehicle Control group
[table 5]
Test compounds Dosage (mg/kg) 3 hours GLP-1 concentration (%ofPre) behind the oral administration
Vehicle Control ??97.5±2.9
Embodiment 229 ??10 ??102.5±1.7
Embodiment 120 ??10 ??104.8±2.9
Metformin ??300 ??108.6±2.2
Metformin+embodiment 229 ??300+10 ??153.7±13.4 ***
Metformin+embodiment 120 ??300+10 ??166.4±16.5 ***
* *: P＜0.001vs vehicle Control group
[table 6]
Test compounds Dosage (mg/kg) 3 hours GLP-1 concentration (%ofPre) behind the oral administration
Vehicle Control ??96.7±2.6
Embodiment 82 ??20 ??97.3±2.1
Embodiment 267 ??10 ??110.0±9.0
Metformin ??300 ??112.5±2.4
Metformin+embodiment 82 ??300+20 ??180.8±23.1 ***
Metformin+embodiment 267 ??300+10 ??186.2±26.2 ***
* *: P＜0.01vs vehicle Control group
When giving metformin or DPPIV inhibitor separately, the concentration of active GLP-1 does not increase.Yet, giving at the same time in the group of metformin and DPPIV inhibitor, the concentration of 3 hours active GLP-1 obviously rises after the administration.This result shows that the rising of active GLP-1 concentration is owing to increase the secretion of GLP-1 by metformin, and suppresses the decomposition of GLP-1 by the DPPIV inhibitor.
[experimental example 5]
The metformin and DPPIV inhibitor (the figured silk fabrics ammonia that in Zucker fa/fa rat, use individually or simultaneously Acid pyrrolidine (Val-Pvr)) to the shadow of glucose tolerance, insulin and GLP-1 concentration, food ration and body weight Ring
Animal: Zucker fa/fa rat, the animal model of type ii diabetes is (available from Charles River Japan, Inc.)
Method:
[preparation of test compounds and give]
Dosage shown in each test compounds following table is dissolved in the distilled water, and gives with the volume per os of 5mL/kg then.The vehicle Control group is that the volume per os with 5mL/kg gives distilled water.Give each test compounds or distilled water with above-mentioned dosage per os, one day twice (at 10:00a.m. and 4:00p.m.) gives 14 days.The glucose tolerance of testing rat in first day in the administration sequence.In this test, gave distilled water and test compounds in preceding 0.5 hour at glucose load.
[determining of the method for blood collection and blood glucose and GLP-1 concentration]
For glucose tolerance test, with the rat of not anesthesia with razor before sever gently and is giving test compounds or distilled water at tail vein place immediately and blood-letting immediately in 0.5,1,2 and 3 hour behind glucose load.The capillary tube that uses heparinization is by gathering the blood of 250 μ L in the rat and being transferred to centrifuge tube.Use Active GLP-1ELISA test kit (Linco) to measure the active GLP-1 concentration of the supernatant that is obtained by centrifuging (in 4 ℃ with centrifugal 2 minutes of 10000g).Simultaneously, gather the blood of 10 μ L and cross the solution chlorate with the 0.6M of 140 μ L and mix.Centrifugal mixture (in 4 ℃ with centrifugal 10 minutes of 3000g), and (Wako Pure ChemicalIndustries Inc.) measures the glucose of the supernatant that is obtained to use Glucose Test Wako II.Independent blood sugar concentration is that 3 hours Measuring Time is determined behind glucose load.
[determining of food ration and body weight]
Food ration and body weight are to measure under the 4:00p.m behind 14 days of administration sequence.Determine total food ration and weight increase in each test group 14 days.
The result:
The result represents with " mean+/-standard error ".Each value of evaluation also compares by the Dunnett test, as showing as shown in the 7-10.
[table 7]
Test compounds dosage (mg/kg) Per os give each time point behind the glucose (hour) GLP-1 concentration (%ofPre)
??-0.5 ??0 ??0.5 ??1 ??2
Vehicle Control ??100.0±0.0 ??101.4±0.8 ??130.5±11.2 ??108.2±2.1 ??101.5±2.0
Metformin (300) ??100.0±0.0 ??105.6±1.7 ??135.4±7.6 ??126.0±8.9 ??118.4±6.5
??Val-Pyr(30) ??100.0±0.0 ??119.5±3.6 ??217.6±24.6 * ??197.5±20.4 * ??128.3±5.4
Metformin (300)+Val-Pyr (30) ??100.0±0.0 ??196.5±11.1 *** ??345.7±40. *** ??262.4±37.0 *** ??272.6±21.2 ***
*: P＜0.05, * *: P＜0.001vs vehicle Control group
[table 8]
Test compounds dosage (mg/kg) Per os give each time point behind the glucose (hour) blood sugar concentration (mg/dl)
??-0.5 ??0 ??0.5 ??1 ??2 ??3
Vehicle Control ??101.4±3.4 ??116.7±3.1 ??199.9±14.5 ??226.9±14.9 ??186.6±8.1 ??120.9±5.4
Metformin (300) ??108.9±5.6 ??117.4±5.5 ??160.6±9.7 * ??177.5±10.6 * ??159.8±8.6 * ??122.4±3.7
??Val-Pyr(30) ??102.6±3.0 ??110.5±3.3 ??166.0±9.9 ??167.1±7.0 *** ??139.3±3.3 *** ??115.1±3.0
Metformin (300)+val-Pyr (30) ??99.0±4.6 ??103.2±3.9 ??119.1±6.6 *** ??125.2±7.2 *** ??114.6±4.5 *** ??104.1±4.2 ***
*: P＜0.05, * *: P＜0.001vs vehicle Control group
[table 9]
Test compounds dosage (mg/kg) Per os give each time point behind the glucose, hour) insulin concentration (ng/ml)
??-0.5 ??0 ??0.5 ??1 ??2
Vehicle Control ??9.8±1.1 ??11.9±1.3 ??22.6±2.0 ??16.2±1.0 ??13.2±0.9
Metformin (300) ??11.9±1.1 ??14.0±1.1 ??22.9±2.5 ??21.2±2.3 ??16.9±1.6
??val-Pyr(30) ??8.8±1.1 ??13.1±1.2 ??32.4±3.2 * ??27.7±5.0 * ??14.4±2.6
Metformin (300)+Val-Pyr (30) ??9.3±1.3 ??14.9±1.4 ??24.3±3.1 ??19.0±2.7 ??15.0±2.9
*: P＜0.05vs vehicle Control group
[table 10]
Test compounds Dosage (mg/kg) Total food ration (g) of 14 days 14 days weight increase (g)
Vehicle Control ??484.2±15.0 ??68.2±4.1
Metformin ??300 ??495.1±8.9 ??64.5±3.5
??Val-Pyr ??30 ??491.8±11.1 ??60.9±4.4
Metformin+Val-Pyr ??300 ??+ ??30 ??418.4±14.0 * ??39.2±6.1 ***
*: P＜0.05, * *: P＜0.001vs vehicle Control group
In the glucose tolerance test process, the concentration of active GLP-1 significantly raises in the group that gives the DPPIV inhibitor, and the concentration of active GLP-1 does not significantly increase in giving the group of metformin simultaneously.Yet the concentration of active GLP-1 gives to increase in collaborative mode in the group of metformin and DPPIV inhibitor at the same time.This result show the concentration of active GLP-1 be by as mentioned above by metformin the excretory increase of inductive GLP-1 and the GLP-1 inhibition of decomposing increase.
This glucose tolerance test be presented at give metformin or DPPIV inhibitor separately each the group in glucose tolerance be improved.Yet,, give at the same time that glucose tolerance improves in collaborative mode in the group of metformin and DPPIV inhibitor when comparing with the group that gives chemical compound separately.
In glucose tolerance test, concentration of insulin increases significantly in the mode of glucose-dependence in the group that gives the DPPIV inhibitor separately, simultaneously give metformin separately or give metformin simultaneously and the group of DPPIV inhibitor in concentration of insulin increase significantly.This result shows that in giving the group of metformin viewed effect is based on outside the pancreas of this medicament and acts on that the effect in the group that gives the DPPIV inhibitor simultaneously is based on because the increase of active GLP-1 concentration makes glucose in the insulin level-dependency increase.On the other hand, it demonstrates the collaborative glucose tolerance that improves owing to the sensitivity that insulin is increased has of the group that gives metformin and DPPIV inhibitor simultaneously, and it is based on the outer effect of pancreas of metformin and by the collaborative increase of the active GLP-1 concentration that administering drug combinations caused.
In addition, give at the same time only to have observed the minimizing of food ration and the inhibition of weight increase in metformin and 14 days the group of DPPIV inhibitor.Can reach a conclusion: use metformin and DPPIV inhibitor owing to unite, make the concentration of active GLP-1 increase synergistically, cause the decline of food ration by hypothalamus, it equally also causes the inhibition of weight increase.
In addition, give at the same time in metformin and 14 days the group of DPPIV inhibitor to find that blood glucose and concentration of insulin reduce synergistically in the fasting process.Give at the same time in the group of metformin and DPPIV inhibitor, because the collaborative improvement of glucose tolerance and the inhibition of weight increase, it is caused by enhanced glucose metabolism effect.This shows uniting use and can treating type ii diabetes effectively of metformin and DPPIV inhibitor.
[experimental example 6]
Metformin is to the influence of GLP-2 concentration in the rat that DPPIV-lacks
The male Fisher rat that animal: DPPIV-lacks is (available from Charles River Japan, Inc.)
Method:
[preparation of test compounds and give]
Test compounds is suspended in 0.5% methocel solution with the dosage shown in the table 11, and gives with the volume per os of 5mL/kg then.The vehicle Control group is that the volume per os with 5mL/kg gives 0.5% methylated cellulose aqueous solution.
[determining of blood collection and GLP-2 concentration]
With the rat of not anesthesia with razor before test compounds or 0.5% methocel solution are severed and given in tail vein place gently and giving blood-letting immediately in 1,3 and 5 hour afterwards.The capillary tube that uses heparinization is by gathering the blood of 250 μ L in the rat and being transferred to centrifuge tube.Use GLP-2ELISA test kit (Yanaihara Institute Inc.) to measure the GLP-2 concentration of the supernatant that is obtained by centrifuging (in 4 ℃ with centrifugal 2 minutes of 10000g).
The result:
The result represents with " mean+/-standard error ".Each value of evaluation and test by t-compares, and is as shown in table 11.
[table 11]
Test compounds Dosage (mg/kg) Each time point behind the oral administration (hour) GLP-2 concentration (ng/ml)
??0 ??1 ??3 ??5
Vehicle Control ??1.39±0.05 ??1.31±0.02 ??1.36±0.04 ??1.28±0.07
Metformin ??300 ??1.32±0.02 ??1.65±0.06 *** ??2.08±0.07 *** ??2.15±0.05 ***
* *: P＜0.001vs vehicle Control group
In giving the group of metformin, in the rat that DPPIV-lacks after the administration in 1,3 and 5 hour the blood plasma concentration of GLP-2 raise significantly.This result shows the effect that use can strengthen GLP-2 synergistically of uniting of metformin and DPPIV inhibitor, and therefore can treat gastrointestinal disease effectively.
[experimental example 7]
Metformin of Shi Yonging and DPPIV inhibitor (valine pyrrolidine (Val-Pyr)) are right individually or simultaneously The influence of the caused little intestinal atrophy of 5-fluorouracil (5-FU)
Animal: BALB/c AnCrj Mus is (available from Charles River Japan, Inc.)
Method:
[preparation of test compounds and give]
5-FU (available from Sigma) is suspended in the solution of 0.5% methylcellulose, and gives (8a.m. to 9a.m.) 3 days (60mg/kg) with 10mL/kg/ days volume per os then.Every kind of test compounds is suspended in the solution of 0.5% methylcellulose with the dosage shown in the table 12, and gives (8a.m. to 9a.m. and 3p.m. to 4p.m.) 2 times with the volume per os of 10mL/kg every day then.The vehicle Control group is that the volume per os with 10mL/kg gives 0.5% methocel solution.The group that will not be subjected to (receive) 5-FU is defined as the normal control group.
[small intestinal sample collecting]
After the 3rd day administration in afternoon of administration sequence, made the Mus fasting 18 hours.At second day, kill Mus by cervical dislocation, and excise whole small intestinal then and measure weight in wet base.
The result:
The result represents with " mean+/-standard error ".Each value of evaluation and test by Tukey compares, and is as shown in Table 12.
[table 12]
5-FU handles (mg/kg) Test compounds Dosage (mg/kg) The weight in wet base of small intestinal (g)
Normal control ??0.700±0.009 **
??60 Vehicle Control ??0.622±0.005
??60 Metformin ??300 ??0.642±0.017
??60 ??Val-Pyr ??30 ??0.637±0.015
??60 Metformin+Val-Pyr ??300 ??+ ??30 ??0.693±0.015 **
*: P＜0.01vs vehicle Control group
5-FU has obviously reduced the weight in wet base of Mus small intestinal.Give the not variation of weight in wet base that metformin or DPPIV inhibitor cause small intestinal in the group of the Mus of handling with 5-FU separately.On the contrary, the administering drug combinations of metformin and DPPIV inhibitor causes the obvious increase of small intestinal weight in wet base.This increase may be caused by uniting the active enhancing of GLP-2 of using metformin and DPPIV inhibitor to be caused.This use of uniting that shows metformin and DPPIV inhibitor can be used for treating gastrointestinal disease, because the increase of GLP-2 concentration causes the growth of apoptotic inhibition and promotion intestinal epithelial cell.
Commercial Application
Comprise that pharmaceutical preparation according to DPPIV inhibitor of the present invention and biguanide reagent can strengthen the effect of active form GLP-2 in active form GLP-1 in the blood and/or the blood, and can be used as the medicine that prevents and/or treats diabetes, obesity, hyperlipemia, gastrointestinal disease etc.In addition, if use is united in pharmaceutical preparation according to the present invention, then each medicament can give with the dosage that the situation that every kind of medicament gives is separately compared still less, and it can reduce the risk of the adverse side effect (for example, the symptom of gastronintestinal system is as diarrhoea) of biguanide reagent.

Claims (34)

1. comprise the pharmaceutical preparation of inhibitors of dipeptidyl IV and biguanide reagent and usefulness.
2. according to the pharmaceutical preparation of claim 1, it can strengthen the effect of active form glucagon-like-peptide-2 (GLP-2) in active form glucagon-like-peptide-1 (GLP-1) in the blood and/or the blood.
3. can strengthen the pharmaceutical preparation of active form GLP-2 effect in the blood.
4. comprise inhibitors of dipeptidyl IV and according to the pharmaceutical preparation of claim 3 and the pharmaceutical preparation of usefulness.
5. according to the pharmaceutical preparation of claim 1 or 4, wherein said inhibitors of dipeptidyl IV is chemical compound or its salt or the hydrate of following formula representative,
Figure A038253940002C1
(wherein,
T 1Contain the monocycle or bicyclo-4-to the 12-element heterocycle base of one or two nitrogen-atoms in the representative ring, it can have one or more substituent groups;
The X representative can have one or more substituent C 1-6Alkyl, can have one or more substituent C 2-6Alkenyl, can have one or more substituent C 2-6Alkynyl, can have one or more substituent C 6-10Aryl, can have one or more substituent 5 to 10-person's heteroaryl, can have one or more substituent C 6-10Aryl C 1-6Alkyl, maybe can have one or more substituent 5 to 10-person's heteroaryl C 1-6Alkyl;
Z 1And Z 2Each represents nitrogen-atoms or formula-CR independently 2The group of=representative;
R 1And R 2Each represents Shi-A independently 0-A 1-A 2Group
(A wherein 0Represent singly-bound or C 1-6Alkylidene, it can have 1-3 substituent group that is selected from the group B that is made up of following substituent group;
A 1Represent group, the formula-group of CO-O-representative, the formula-NR of singly-bound, oxygen atom, sulphur atom, sulfinyl, sulfonyl, carbonyl, formula-O-CO-representative AThe group of-representative, formula-CO-NR AThe group of-representative, formula-NR AThe group of-CO-representative, formula-SO 2-NR AThe group of-representative or formula-NR A-SO 2The group of-representative;
A 2And R AEach represents hydrogen atom, halogen atom, cyano group, C independently 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 6-10Aryl, 5 to 10-person's heteroaryl, 4 to 8-element heterocycle bases, 5 to 10-person's heteroaryl C 1-6Alkyl, C 6-10Aryl C 1-6Alkyl or C 2-7Alkyl-carbonyl;
Yet, A 2And R AEach can have 1-3 substituent group that is selected from the basis set B of following replacement independently:
Work as Z 2Be formula-CR 2During the group of=representative, R 1And R 2Can form 5 jointly encircles to 7-person;
Except following situation: [1] R 1Be hydrogen atom; Z 1Be nitrogen-atoms; And Z 2For-CH=; [2] Z 1Be nitrogen-atoms; And Z 2For-C (OH)=;
＜replace basis set B 〉
Replace basis set B and represent following groups: hydroxyl, sulfydryl, cyano group, nitro, halogen atom, trifluoromethyl, can have one or more substituent C 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 6-10Aryl, 5 is to 10-person's heteroaryl, 4 to 8-element heterocycle bases, C 1-6Alkoxyl, C 1-6Alkylthio group, formula-SO 2-NR B1-R B2The group of representative, formula-NR B1-CO-R B2The group of representative, formula-NR B1-R B2(R wherein B1And R B2Each represents hydrogen atom or C independently 1-6Alkyl) group of representative, formula-CO-R B3(R wherein B3Represent 4 to 8-element heterocycle bases) group, the formula-CO-R of representative B4-R B5The group of representative and formula-CH 2-CO-R B4-R B5The group of representative (R wherein B4Represent singly-bound, oxygen atom or formula-NR B6The group of-representative; R B5And R B6Each represents hydrogen atom, C independently 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 6-10Aryl, 5 is to 10-person's heteroaryl, 4 to 8-element heterocycle C 1-6Alkyl, C 6-10Aryl C 1-6Alkyl or 5 is to 10-person's heteroaryl C 1-6Alkyl)).
6. according to the pharmaceutical preparation of claim 5, T wherein 1Be piperazine-1-base or 3-amino-piperadine-1-base.
7. according to the pharmaceutical preparation of claim 5, T wherein 1Be piperazine-1-base.
8. according to any one pharmaceutical preparation among the claim 5-7, wherein X is 3-methyl-2-butene-1-base, 2-butyne base, benzyl or 2-chlorphenyl.
9. according to any one pharmaceutical preparation among the claim 5-7, wherein X is the 2-butyne base.
10. according to any one pharmaceutical preparation among the claim 5-9, wherein,
Z 1It is nitrogen-atoms; With
Z 2Be formula-CR 2The group of=representative,
(R wherein 2As defined in claim 5).
11. according to any one pharmaceutical preparation among the claim 5-9, wherein,
Z 2It is nitrogen-atoms; With
Z 1Be formula-CR 2The group of=representative,
(R wherein 2As defined in claim 5).
12. according to any one pharmaceutical preparation, wherein R among the claim 5-11 1Be methyl, cyano group benzyl, fluoro cyano group benzyl, phenethyl, 2-methoxy ethyl or 4-methoxycarbonyl pyridine-2-base.
13. according to any one pharmaceutical preparation, wherein R among the claim 5-11 1Be methyl or 2-cyano group benzyl.
14. according to any one pharmaceutical preparation, wherein R among the claim 5-13 2Be the group of hydrogen atom, cyano group, methoxyl group, carbamyl phenoxyl or following formula representative:
Or
Figure A038253940004C2
(wherein, A 27Represention oxygen atom, sulphur atom or-NH-; A 28And A 29Each represents hydrogen atom or C independently 1-6Alkyl).
15. according to any one pharmaceutical preparation, wherein R among the claim 5-13 2Be hydrogen atom, cyano group or 2-carbamyl phenoxyl.
16. according to the pharmaceutical preparation of claim 5, the chemical compound of its Chinese style (I) representative is to be selected from following one of any chemical compound:
(1) 7-(2-butyne base)-2-cyano group-1-methyl-8-(piperazine-1-yl)-1,7-dihydro purine-6-one;
(2) 3-(2-butyne base)-5-methyl-2-(piperazine-1-yl)-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone also;
(3) 2-(3-amino piperidine-1-yl)-3-(2-butyne base)-5-methyl-3, the 5-glyoxalidine is [4,5-d] pyridazine-4-ketone also;
(4) 2-[7-(2-butyne base)-1-methyl-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-base oxygen base] benzamide;
(5) 7-(2-butyne base)-1-(2-cyano group benzyl)-6-oxo-8-(piperazine-1-yl)-6,7-dihydro-1H-purine-2-nitrile; With
(6) 2-[3-(2-butyne base)-4-oxo-2-(piperazine-1-yl)-3, the 4-glyoxalidine is [4,5-d] pyridazine-5-ylmethyl also] benzonitrile;
Or its salt or hydrate.
17. according to the pharmaceutical preparation of claim 1 or 4, wherein said inhibitors of dipeptidyl IV is chemical compound or its salt or the hydrate of following formula representative,
Figure A038253940005C1
(T wherein 1, X, R 1And R 2As defined in claim 5).
18. according to the pharmaceutical preparation of claim 17, wherein T 1Be piperazine-1-base.
19. according to the pharmaceutical preparation of claim 17 or 18, wherein X is 2-butyne base or 2-chlorphenyl.
20. according to the pharmaceutical preparation of claim 17 or 18, wherein X is the 2-butyne base.
21. according to any one pharmaceutical preparation, wherein R among the claim 17-20 1Group for hydrogen atom, methyl, 2-propynyl, 2-butyne base, cyano methyl, phenethyl, phenoxy group ethyl or following formula representative:
Figure A038253940005C2
(R wherein 3Representation hydroxy, C 1-6Alkoxyl or phenyl).
22. according to any one pharmaceutical preparation, wherein R among the claim 17-21 2Be hydrogen atom, C 1-6The group of alkyl, ethoxyethyl group, oxolane ylmethyl or following formula representative:
(wherein, R 4And R 5Be same to each other or different to each other, and represent hydrogen atom independently, methyl or phenyl; And R 6Representation hydroxy, C 1-6Alkoxyl or phenyl),
Or the group of following formula representative:
Figure A038253940005C4
23. according to the pharmaceutical preparation of claim 17, the chemical compound of its Chinese style (II) representative is to be selected from one of following chemical compound:
(1) 7-(2-butyne base)-1,3-dimethyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(2) 7-(2-butyne base)-3-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(3) [7-(2-butyne base)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-yl] methyl acetate;
(4) 7-(2-butyne base)-3-methyl-8-(piperazine-1-yl)-1-(2-propynyl)-3,7-dihydro purine-2,6-diketone;
Two (2-butyne the base)-3-methyl-8-(piperazine-1-yl)-3 of (5) 1,7-, 7-dihydro purine-2,6-diketone;
(6) [7-(2-butyne base)-3-methyl-2,6-dioxo-8-(piperazine-1-yl)-2,3,6,7-tetrahydrochysene purine-1-yl] acetonitrile;
(7) 7-(2-butyne base)-3-methyl isophthalic acid-[(2-oxo-2-phenyl) ethyl]-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(8) 7-(2-butyne base)-3-ethyl-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(9) [7-(2-butyne base)-1-methyl-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] methyl acetate;
(10) 7-(2-butyne base)-3-(2-tetrahydrofuran base) methyl isophthalic acid-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(11) [7-(2-butyne base)-1-methyl-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] phenylacetic acid methyl ester;
(12) 7-(2-butyne base)-3-propyl group-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(13) 7-(2-butyne base)-3-(2-oxo-2-phenethyl)-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(14) 2-[7-(2-butyne base)-1-methyl-2,6-dioxo-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] ethyl propionate;
(15) 7-(2-butyne base)-3-(2-ethoxyethyl group)-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(16) 7-(2-butyne base)-3-isopropyl-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(17) 7-(2-butyne base)-3-(3,3-dimethyl-2-oxo butyl)-1-methyl-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(18) 7-(2-butyne base)-1-methyl-3-(2-oxo-pyrrolidine-3-yl)-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(19) 7-(2-butyne base)-3-(2-ethoxyethyl group)-1-(2-oxo-2-phenylethyl)-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(20) [7-(2-butyne base)-2,6-dioxo-1-(2-oxo-2-phenylethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] methyl acetate;
(21) [7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] ethyl acetate;
(22) [7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl] acetas;
(23) 7-(2-butyne base)-3-[2-oxo-2-(pyrrolidine-1-yl) ethyl]-1-(2-phenethyl)-8-(piperazine-1-yl)-3,7-dihydro purine-2,6-diketone;
(24) 2-[7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl]-the N-methylacetamide;
(25) 2-[7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl]-N-cyclopropyl acetamide;
(26) 2-[7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl]-the N-phenyl acetamide; With
(27) 2-[7-(2-butyne base)-2,6-dioxo-1-(2-phenethyl)-8-(piperazine-1-yl)-1,2,6,7-tetrahydrochysene purine-3-yl]-N-(2-propynyl) acetamide;
Or its salt or hydrate.
24. according to the pharmaceutical preparation of claim 1, wherein this biguanide reagent is metformin.
25. according to the pharmaceutical preparation of claim 1 or 2, it is the medicine of the disease that active form GLP-2 is relevant in active form GLP-1 in prevention or treatment and the blood and/or the blood.
26. according to the pharmaceutical preparation of claim 25, wherein said disease be selected from following any at least: diabetes, obesity, hyperlipemia and gastrointestinal disease.
27. according to the pharmaceutical preparation of claim 3 or 4, it is the medicine of prevention or the treatment disease relevant with active form GLP-2 in the blood.
28. according to the pharmaceutical preparation of claim 27, wherein this disease is a gastrointestinal disease.
29. comprising with effective dose, the method for the disease that active form GLP-2 is relevant in active form GLP-1 and/or the blood in prevention or treatment and the blood, described method give pharmaceutical preparation according to claim 1 or 2.
30. according to the pharmaceutical preparation of claim 1 or 2 preparation be used for preventing or the medicine of the disease that treatment is relevant with active form GLP-2 in blood active form GLP-1 and/or the blood in purposes.
31. one kind is used for preventing or the method for the disease that treatment is relevant with blood active form GLP-2, described method comprises with effective dose and gives pharmaceutical preparation according to claim 3 or 4.
32. according to the pharmaceutical preparation of claim 3 or 4 preparation be used for preventing or the medicine of the disease that treatment is relevant with blood active form GLP-2 in purposes.
33. a method that strengthens active form GLP-2 effect in active form GLP-1 in the blood and/or the blood, described method comprises the pharmaceutical preparation of use according to claim 1 or 2.
34. a method that strengthens active form GLP-2 effect in the blood, described method comprises the pharmaceutical preparation of use according to claim 3 or 4.
CN 03825394 2002-09-26 2003-09-22 Combination drug Pending CN1700911A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103172633A (en) * 2011-12-22 2013-06-26 成都地奥制药集团有限公司 Compound, and preparation method and application thereof
CN103261200A (en) * 2010-09-13 2013-08-21 阿迪维纳斯疗法有限公司 Purine compounds as prodrugs of a2b adenosine receptor antagonists, their process and medicinal applications
CN114727983A (en) * 2019-09-25 2022-07-08 金翅雀生物公司 Xanthine CB1 inhibitors

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103261200A (en) * 2010-09-13 2013-08-21 阿迪维纳斯疗法有限公司 Purine compounds as prodrugs of a2b adenosine receptor antagonists, their process and medicinal applications
CN103261200B (en) * 2010-09-13 2016-03-30 阿迪维纳斯疗法有限公司 As the purine compound of the prodrug of A2B adenosine receptor antagonists, their preparation method and medicinal use
CN103172633A (en) * 2011-12-22 2013-06-26 成都地奥制药集团有限公司 Compound, and preparation method and application thereof
CN114727983A (en) * 2019-09-25 2022-07-08 金翅雀生物公司 Xanthine CB1 inhibitors

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