CN103254192B - Xanthine derivative, its salt, intermediate, preparation method and application - Google Patents
Xanthine derivative, its salt, intermediate, preparation method and application Download PDFInfo
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- CN103254192B CN103254192B CN201210034066.3A CN201210034066A CN103254192B CN 103254192 B CN103254192 B CN 103254192B CN 201210034066 A CN201210034066 A CN 201210034066A CN 103254192 B CN103254192 B CN 103254192B
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- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 150000003839 salts Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 102000004190 Enzymes Human genes 0.000 claims abstract description 16
- 108090000790 Enzymes Proteins 0.000 claims abstract description 16
- 230000000694 effects Effects 0.000 claims abstract description 12
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 9
- 239000003112 inhibitor Substances 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 201000001421 hyperglycemia Diseases 0.000 claims abstract description 4
- 206010022489 Insulin Resistance Diseases 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 168
- -1 xanthine compound Chemical class 0.000 claims description 160
- 150000001875 compounds Chemical class 0.000 claims description 139
- 238000006243 chemical reaction Methods 0.000 claims description 83
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 51
- 238000000034 method Methods 0.000 claims description 50
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 45
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- 238000002156 mixing Methods 0.000 claims description 33
- 229940075420 xanthine Drugs 0.000 claims description 32
- 239000003880 polar aprotic solvent Substances 0.000 claims description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims description 21
- 238000004440 column chromatography Methods 0.000 claims description 20
- 239000012044 organic layer Substances 0.000 claims description 20
- 150000003512 tertiary amines Chemical class 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 19
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 18
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 claims description 17
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 16
- 150000001412 amines Chemical class 0.000 claims description 16
- 125000006504 o-cyanobenzyl group Chemical group [H]C1=C([H])C(C#N)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 15
- 230000009471 action Effects 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 14
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 13
- 239000003513 alkali Substances 0.000 claims description 13
- 229910052783 alkali metal Inorganic materials 0.000 claims description 13
- 150000001340 alkali metals Chemical class 0.000 claims description 13
- 238000003328 mesylation reaction Methods 0.000 claims description 13
- 125000006239 protecting group Chemical group 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 10
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 229910021529 ammonia Inorganic materials 0.000 claims description 9
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 229960004275 glycolic acid Drugs 0.000 claims description 8
- 229960000789 guanidine hydrochloride Drugs 0.000 claims description 8
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical group CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 7
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 7
- 239000010410 layer Substances 0.000 claims description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 6
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 claims description 6
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 150000001339 alkali metal compounds Chemical class 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- ZXVOCOLRQJZVBW-UHFFFAOYSA-N azane;ethanol Chemical compound N.CCO ZXVOCOLRQJZVBW-UHFFFAOYSA-N 0.000 claims description 2
- 150000003840 hydrochlorides Chemical group 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- QARBMVPHQWIHKH-KHWXYDKHSA-N methanesulfonyl chloride Chemical group C[35S](Cl)(=O)=O QARBMVPHQWIHKH-KHWXYDKHSA-N 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 abstract description 13
- 238000012827 research and development Methods 0.000 abstract description 3
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- 239000007858 starting material Substances 0.000 description 14
- 230000008034 disappearance Effects 0.000 description 13
- 238000010626 work up procedure Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 7
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
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- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
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- MWXFBYOMAQPKEK-UHFFFAOYSA-N 8-(hydroxymethyl)-3-methyl-7h-purine-2,6-dione Chemical compound O=C1NC(=O)N(C)C2=C1NC(CO)=N2 MWXFBYOMAQPKEK-UHFFFAOYSA-N 0.000 description 3
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 3
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of xanthine derivative or its salt, its preparation method and preparing the application treated and/or prevented in the medicine of non-insulin-dependent diabetes mellitus (NIDDM), hyperglycemia or insulin resistance; With it at preparation DPP-4 activity inhibitor, or by suppressing DPP-4 enzyme treatment and/or preventing the application in the medicine of relative disease.In addition, the invention also discloses the intermediate in formula I preparation method.Xanthine derivative of the present invention and salt thereof are that the research and development of DPP-4 inhibitor provide a new direction, significant to exploitation DPP-4 inhibitor.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a xanthine compound, an intermediate thereof, pharmaceutically acceptable salts thereof, a preparation method thereof and application thereof.
Background
Diabetes is a serious disease threatening the health of humans. According to the world health organization, about 1.8 hundred million diabetics exist in the world, 90% of them are type 2 diabetes, and the number is predicted to be doubled by 2030. At present, the treatment of type 2 diabetes mainly comprises small molecular oral drugs, and sulfonylureas, meglitinides, biguanides and thiazolidinediones are common treatment drugs for type 2 diabetes, but long-term use of the hypoglycemic drugs can cause adverse reactions of hypoglycemia, weight gain, beta-cell functional injury and the like of patients. The discovery of the DPP-4 inhibitor can effectively avoid the defects of the traditional oral hypoglycemic drugs, and DPP-4 is generally considered as the most promising new target for treating type 2 diabetes.
DPP-4 is also called CD26, and is firstly separated from rat liver in 1966, and the protein three-dimensional structure of DPP-4 is determined in 2003, and DPP-4 is high-specificity serine protease existing in a dimer form, and natural substrates of DPP-4 are glucagon-like peptide-1 (GLP-1) and Glucose Insulinotropic Polypeptide (GIP). GLP-1 has glucose-dependent insulinotropic secretion, glucagon secretion inhibition, islet beta cell regeneration and repair promotion, postprandial gastric emptying delay and other functions, and GIP also has insulinotropic secretion function. DPP-4 can rapidly degrade and inactivate GLP-1 and GIP in vivo. The DPP-4 inhibitor reduces the catalytic activity of enzyme by competitively binding with DPP-4 activation site, thereby increasing the amount of GLP-1 and GIP in vivo to achieve the effect of promoting insulin secretion. The DPP-4 inhibitor can stably control blood sugar, improve beta cell function, does not cause the weight increase of patients, can avoid the risk of hypoglycemia, has obvious advantages in the aspect of medication safety, and is a promising medicament.
Since the report of the crystal structure of DPP-4 in 2003, many DPP-4 inhibitors of new structural type, potent and high selectivity have been introduced into the market successively in recent years, such as sitagliptin phosphate developed by merck (sitagliptophosphate, marketed in the us 2006 month 10), vildagliptin developed by nover (vildagliptin, approved by the european union in 2007 month 9) and saxagliptin developed by baishinobao corporation in cooperation with astrazep (saxagliptin, approved for marketing in us 2009 8 month us), argliptin benzoate (alogliptininzoate, marketed in japan 2010 month 4) of martian and Linagliptin (Linagliptin) of brilinger (boehringer ingenheim) (2011-1356, BI marketed in us 20115 month BI).
At present, DPP-4 inhibitors containing amino cycloalkane or piperazine segments become a new direction for developing hypoglycemic drugs. Therefore, the research on the compounds with novel structures and piperidine or piperazine fragments has important significance for developing potential DPP-4 inhibitors.
Disclosure of Invention
The invention aims to provide a xanthine compound, salt and intermediate thereof, a preparation method and application thereof. The xanthine compound and the salt thereof provide a new direction for the research and development of the DPP-4 inhibitor, and have important significance for developing potential DPP-4 inhibitors.
The invention provides a xanthine compound shown as a formula I or a pharmaceutically acceptable salt thereof,
wherein,
R1is a bicyclic aromatic substituent, as shown in formula VII, A and B are independently C or N, R4Is H, CH3、OCH3Or 4-fluorophenylthio, R5、R6And R7Independently H, Cl or F, said substituent of formula VII being attached to the compound of formula I via the 1, 2 or 3 position;
R2is 2-cyanobenzyl or but-2-ynyl;
R3is composed ofn = 2-4, amino, guanidino orm = 2-3, D is H or NH2E is CH2NH or CHNH2。
Said R1Preferred are naphthalen-1-yl, 4-methylquinazolin-2-yl, 6-fluoro-7-chloro-4-methoxyquinolin-3-yl and 6,7, 8-trifluoro-4- (4-fluorophenylthio) quinolin-3-yl.
Said R3Preferably amino, guanidino, 2-aminoethylamino, 3-aminopropylamino, 4-aminobutylamino, R-3-aminopiperidin-1-yl, piperazin-1-yl, homopiperazin-1-yl or 4-aminopiperidin-1-yl.
When R is1Is 4-methyl-quinazolin-2-yl and R2When it is but-2-ynyl, R3Preferably R-3-aminopiperidin-1-yl, 2-aminoethylamino, piperazin-1-yl, homopiperazin-1-yl, 4-aminopiperidin-1-yl, 3-aminopropylamino or 4-aminobutylamino, more preferably R-3-aminopiperidin-1-yl, 2-aminoethylamino, piperazin-1-yl or homopiperazin-1-yl;
when R is1Is naphthalen-1-yl and R2When it is but-2-ynyl, R3Preferably R-3-aminopiperidin-1-yl, 2-aminoethylamino, piperazin-1-yl, homopiperazin-1-yl, 4-aminopiperidin-1-yl or guanidino, more preferably piperazin-1-yl;
when R is1Is naphthalen-1-yl and R2In the case of 2-cyanobenzyl, R3Preferably R-3-aminopiperidin-1-yl, 2-aminoethylamino, piperazin-1-yl, homopiperazin-1-yl or 4-aminopiperidin-1-yl, more preferably homopiperazin-1-yl or 4-aminopiperidin-1-yl;
when R is1Is 4-methyl-quinazolin-2-yl and R2In the case of 2-cyanobenzyl, R3Preferably R-3-aminopiperidin-1-yl, 2-aminoethylamino, piperazin-1-yl, homopiperazin-1-yl, 4-aminopiperidin-1-yl or amino, more preferably R-3-aminopiperidin-1-yl or 2-aminoethylamino;
when R is1Is 6,7, 8-trifluoro-4- (4-fluorophenylthio) quinolin-3-yl and R2When it is but-2-ynyl, R3Preferably R-3-aminopiperidin-1-yl or 2-aminoethylamino;
when R is1Is 6-fluoro-7-chloro-4-methoxyquinolin-3-yl and R2When it is but-2-ynyl, R3Preferably 2-aminoethylamino, piperazin-1-yl, homopiperazin-1-yl, 3-aminopropylamino, 4-aminobutylamino or amino.
The salt is preferably a hydrochloride, sulfate, hydrobromide, acetate, phosphate or benzoate salt, more preferably a hydrochloride, phosphate or benzoate salt. The hydrochloride and/or phosphate salts are preferably present in the form of hydrates. The hydrate may be a monohydrate or a hemihydrate.
The invention also provides a preparation method of the xanthine compound shown in the formula I,
when said R is3Is composed ofn = 2-4, amino group,m = 2-3, E is NH and D is H, it includes the following steps: reacting a compound of formula II with R in a polar aprotic solvent at 20 ℃ to 30 ℃3H, carrying out nucleophilic substitution reaction;
wherein R is1And R2All as described above;
when said R is3Is composed ofm =2, D is NH2And E is CH2When the method is used, the method comprises the following steps: firstly, performing nucleophilic substitution reaction on a compound shown in a formula II and R-3-tert-butoxy acyl amino piperidine in a polar aprotic solvent at the temperature of 20-30 ℃ under the action of tertiary amine, and performing post-treatment on a product subjected to the nucleophilic substitution reaction; secondly, performing tert-butoxy acyl protecting group removing reaction on the post-treated product obtained in the step I to obtain a compound shown in the formula I;
wherein R is1And R2All as described above;
when said R is3Is composed ofm =2, D is H and E is CHNH2When the method is used, the method comprises the following steps: firstly, performing nucleophilic substitution reaction on a compound shown in a formula II and 4-phthaloylaminopiperidine in a polar aprotic solvent at the temperature of 20-30 ℃ under the action of tertiary amine, and performing post-treatment on a product after the nucleophilic substitution reaction; secondly, performing phthaloyl protecting group removing reaction on the post-treated product obtained in the step I to obtain a compound shown in the formula I;
wherein R is1And R2All as described above;
when said R is3When guanidino, it comprises the following steps: performing nucleophilic substitution reaction on guanidine hydrochloride and a compound shown in a formula II in an alcohol solvent at the reaction temperature of 20-60 ℃ under the action of alkali to obtain the compound shown in the formula I;
formula II formula I
Wherein R is1And R2All as described above.
When said R is3Is composed ofn = 2-4, amino group,m = 2-3, E is NH and D is H, the process for the preparation of the compound of formula i preferably comprises the following steps: at 20-30 ℃, R is reacted3Dissolving H in polar aprotic solvent, mixing with the compound of formula II, and carrying out nucleophilic substitution reaction.
Wherein, when said R is3When H is ethylenediamine, homopiperazine, 1, 3-propanediamine, 1, 4-butanediamine or piperazine, the molar ratio of H to the compound of formula II is preferably 2:1 to 10:1, more preferably 5:1 to 10: 1. When R is3When it is amino, R is3H preferably takes part in the reaction in the form of an ethanolic solution of ammonia. The molar ratio of ammonia to the compound shown in the formula II in the ammonia ethanol solution is preferably 2: 1-50: 1, and more preferably 2: 1-20: 1. The polar aprotic solvent is preferably dichloromethane. The dosage of the solvent is not influenced by the normal reaction, and preferably 5-10 ml/g of the compound shown in the formula II. The compound of formula II is preferably R2When it is but-2-ynyl, R1Is 4-methyl quinazolin-2-yl, naphthalen-1-yl, 6,7, 8-trifluoro-4- (4-fluorophenylthio) quinolin-3-yl or 7-chloro-6-fluoro-4-methoxyquinolin-3-yl; or when R is2In the case of 2-cyanobenzyl, R1Is 4-methyl quinazoline-2-yl or naphthalene-1-yl. The concentration of the ethanol solution of ammonia may be selected from the concentration of ethanol solutions of ammonia commonly used in the art, and is preferably 10mol/L to 15 mol/L. The progress of the nucleophilic substitution reaction can be monitored by TLC or HPLC, and is generally the end point of the reaction when the compound of formula II disappears. Said nucleophilic reaction may be followed by a work-up procedure to further purify the resulting compound of formula I, which preferably comprises the following work-up steps: and mixing the reaction system with dichloromethane, washing the organic layer with water, drying with anhydrous sodium sulfate, and concentrating. When said R is3In the case of amino groups, the work-up procedure may also include recrystallization. The solvent used for recrystallization is preferably ethanol. The dosage of the ethanol used for recrystallization is preferably 18-25 ml/g of the compound shown in the formula II.
When said R is3Is composed ofm =2, D is NH2And E is CH2The process for the preparation of said compounds of formula i preferably comprises the following steps: dissolving R-3-tert-butoxy acyl amino piperidine and tertiary amine in polar aprotic solvent at 20-30 deg.c, adding into compound of formula IICarrying out nucleophilic substitution reaction, and carrying out post-treatment on a product subjected to the nucleophilic substitution reaction; dissolving the post-treated product obtained in the step I in a polar aprotic solvent at the temperature of 20-30 ℃, mixing the solution with a reagent for removing the tert-butoxy acyl protecting group, and carrying out the reaction for removing the tert-butoxy acyl protecting group to obtain the compound shown in the formula I.
In the step (I), triethylamine is preferably used as the tertiary amine. The molar ratio of the tertiary amine to the compound of the formula II is preferably 1.1: 1-1.5: 1. The polar aprotic solvent is preferably dichloromethane. The dosage of the polar aprotic solvent does not influence the normal reaction, and preferably 5-10 ml/g of the compound of the formula II. The molar ratio of the R-3-tert-butoxy acyl amino piperidine to the compound shown in the formula II is preferably 1.0: 1-1.5: 1. The progress of the nucleophilic substitution reaction can be monitored by TLC or HPLC, and is generally the end point of the reaction when the compound of formula II disappears. The work-up may be a work-up procedure conventional in the art, in order to remove impurities from the product in order to purify the product, and preferably comprises the following steps: mixing the reaction system with dichloromethane and water, separating an organic layer, drying with anhydrous sodium sulfate, and concentrating.
Wherein, in the step (II), the polar aprotic solvent is preferably dichloromethane. The dosage of the polar aprotic solvent does not influence the normal reaction, and preferably 5-10 ml/g of the compound of the formula II. The reagent for removing the tert-butoxy acyl protecting group can be selected from the reagent for removing the tert-butoxy acyl protecting group, which is known by the technical personnel in the field and is suitable for the invention, and trifluoroacetic acid is preferred. The molar ratio of the tert-butoxy acyl protecting group removing reagent to the compound shown in the formula II is preferably 5: 1-25: 1. The progress of the reaction for removing the tert-butoxy acyl protecting group can be monitored by TLC or HPLC, and is generally used as the end point of the reaction when the post-treated product obtained in the step (i) disappears. The reaction for removing the tert-butoxy acyl protecting group can be further followed by post-treatment to further obtain the pure compound shown in the formula I. The post-treatment preferably comprises the following steps: mixing the reaction system with saturated sodium carbonate aqueous solution until the water layer is alkaline, sequentially extracting with dichloromethane, washing with saturated saline solution, combining organic layers, drying with anhydrous sodium sulfate, and concentrating.
When said R is3Is composed ofm =2, D is H and E is CHNH2The process for the preparation of said compounds of formula i preferably comprises the following steps: dissolving 4-phthaloylaminopiperidine and tertiary amine in a polar aprotic solvent at 20-30 ℃, adding the mixture into a compound in a formula II to perform nucleophilic substitution reaction, and performing post-treatment on a product after the nucleophilic substitution reaction; dissolving the post-treated product obtained in the step I in a polar aprotic solvent at the temperature of 20-30 ℃, mixing the solution with a phthaloyl protecting group removing reagent, and performing a phthaloyl protecting group removing reaction to obtain the compound shown in the formula I.
In the step (I), triethylamine is preferably used as the tertiary amine. The molar ratio of the tertiary amine to the compound of the formula II is preferably 1.1: 1-1.5: 1. The polar aprotic solvent is preferably dichloromethane. The dosage of the polar aprotic solvent does not influence the normal reaction, and preferably 5-10 ml/g of the compound of the formula II. The mol ratio of the 4-phthaloylaminopiperidine to the compound of the formula II is preferably 1.0:1 to 1.5: 1. The progress of the nucleophilic substitution reaction can be monitored by TLC or HPLC, and is generally the end point of the reaction when the compound of formula II disappears. The work-up may be a work-up procedure conventional in the art, in order to remove impurities from the product in order to purify the product, and preferably comprises the following steps: mixing the reaction system with water and dichloromethane, separating organic layer, extracting water layer with dichloromethane, mixing organic layers, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography. Wherein, the conditions and the operation steps of the column chromatography can refer to the conditions and the operation steps of the column chromatography which are conventional in the field.
Wherein, in the step (II), the polar aprotic solvent is preferably dichloromethane. The dosage of the polar aprotic solvent does not influence the normal reaction, and preferably 5-10 ml/g of the compound of the formula II. The agent for dephthaloyl protecting group may be selected from those known to those skilled in the art to be suitable for use in the present invention, preferably ethanolamine. The molar ratio of the phthaloyl protecting group removing reagent to the compound shown in the formula II is preferably 2: 1-40: 1, and more preferably 2: 1-20: 1. The progress of the reaction for removing the phthaloyl protecting group can be monitored by TLC or HPLC, and is generally used as the end point of the reaction when the post-treated product obtained in the step (i) disappears. The reaction for removing the phthaloyl protecting group can be followed by post-treatment to further obtain the pure compound of the formula I. The post-treatment preferably comprises the following steps: mixing the reaction system with water and dichloromethane, separating organic layer, extracting water layer with dichloromethane, mixing organic layers, washing with water, drying organic layer with anhydrous sodium sulfate, and concentrating.
When said R is3In the case of guanidino, the process for the preparation of said compounds of formula I preferably comprises the following steps: dissolving guanidine hydrochloride and alkali in an alcohol solvent at the reaction temperature of 20-60 ℃, and adding a compound shown in a formula II to perform nucleophilic substitution reaction to obtain the compound shown in the formula I.
Wherein, the alkali can be selected from the alkali which is known by the technical personnel and is applicable to the invention, and the alkali metalate of alcohol is preferred. The alkali metal compound of the alcohol is preferably sodium tert-butoxide or potassium tert-butoxide. The molar ratio of the alkali to the compound of the formula II is preferably 1: 1-10: 1, and more preferably 1: 1-5: 1. The alcohol solvent is preferably tert-butanol. The dosage of the alcohol solvent is not required to influence the normal reaction, and preferably 5-10 ml/g of the compound shown in the formula II. The molar ratio of the guanidine hydrochloride to the compound shown in the formula II is preferably 1: 1-5: 1, and more preferably 1: 1-3: 1. The reaction temperature is preferably 40 ℃ to 60 ℃. The progress of the nucleophilic substitution reaction can be monitored by TLC or HPLC, and is generally the end point of the reaction when the compound of formula II disappears. The nucleophilic substitution reaction may also be followed by a work-up procedure to further purify the resulting compound of formula I, which preferably comprises the following steps: mixing the reaction system with water and dichloromethane, separating organic layer, extracting water phase with dichloromethane, mixing organic phases, washing with water, drying the organic phase with anhydrous sodium sulfate, concentrating, and performing column chromatography. Wherein, the conditions and the operation steps of the column chromatography can refer to the conditions and the operation steps of the column chromatography which are conventional in the field.
The compound of the formula II can be prepared by the following method:
(1) taking water as a solvent, and carrying out condensation reaction on a compound shown in a formula VI and hydroxyacetic acid under the action of hydroxide of alkali metal, wherein the reaction temperature is 20-100 ℃;
(2) taking DMSO as a solvent, and reacting the compound of the formula V with R under the action of organic amine2Carrying out 7-site nucleophilic substitution reaction on the X to obtain a compound shown in a formula IV, wherein the reaction temperature is 20-30 ℃;
(3) taking DMF as a solvent, and reacting a compound shown in the formula IV with R under the action of carbonate of alkali metal1CH2Carrying out 1-site nucleophilic substitution reaction on the X to obtain a compound shown in a formula III, wherein the reaction temperature is 20-60 ℃;
(4) taking dichloromethane as a solvent, and carrying out mesylation reaction on a compound shown in a formula III and a mesylation reagent under the action of organic amine to obtain a compound shown in a formula II, wherein the reaction temperature is 0-30 ℃;
wherein, R is1And R2All as described above; x is Cl, Br, I.
In the step (1), it is preferable to include the following steps: dissolving the compound shown in the formula VI in water at the temperature of between 20 and 100 ℃, mixing the mixture with glycolic acid, reacting for 0.5 to 2 hours, mixing the mixture with hydroxide of alkali metal, and carrying out condensation reaction. The hydroxide of the alkali metal is preferably sodium hydroxide. The alkali metal hydroxide is preferably reacted in the form of an aqueous solution. The concentration of the aqueous solution of the alkali metal hydroxide is preferably 3.0 to 4.5mol/L, more preferably 3.5 to 4.0 mol/L. The molar ratio of the alkali metal hydroxide to the compound of formula VI is preferably 1.1:1 to 3:1, more preferably 1.5:1 to 2: 1. The dosage of the solvent is enough not to influence the normal reaction, preferably 2-6 ml/g of the compound shown in the formula VI, and more preferably 3-4 ml/g of the compound shown in the formula VI. The molar ratio of the glycolic acid to the compound of the formula VI is preferably 2: 1-4: 1, and more preferably 2: 1-3: 1. The reaction temperature is preferably 50 ℃ to 100 ℃, more preferably 80 ℃ to 100 ℃. The progress of the condensation reaction can be monitored by TLC or HPLC, and is generally the end point of the reaction when the compound of formula VI disappears. Said condensation reaction may also be followed by a work-up procedure to further purify the resulting compound of formula v, which preferably comprises the following steps: cooling the reaction system to room temperature (20-30 ℃), filtering, and recrystallizing the filter cake with water.
In the step (2), it is preferable to include the following steps: dissolving the compound of formula V in DMSO at 20-30 deg.C, mixing with organic amine, adding R2And carrying out 7-site nucleophilic substitution reaction on the X to obtain the compound shown in the formula IV. The organic amine may be selected from organic amines known to those skilled in the art to be suitable for use in the present invention, preferably diisopropylethylamine. The mol ratio of the organic amine to the compound of the formula V is preferably 1: 1-2: 1. The compound of the formula V and R2The molar ratio of X is preferably 1:1 to 2: 1. The DMSO is used in an amount which does not affect the normal reaction, and the preferable amount is 6-10 ml/g of the compound of the formula V. The progress of the nucleophilic substitution at the 7-position can be monitored by TLC or HPLC, and is generally the end point of the reaction when the compound of formula V disappears. Said nucleophilic substitution at the 7-position may be followed by a work-up procedure to further purify the compound of formula iv, which preferably comprises the steps of: when said R is2And (3) mixing the reaction system with dichloromethane when the reaction system is the butyl-2-alkynyl, and performing suction filtration to obtain the product. The volume ratio of the dichloromethane to the DMSO is preferably 15: 1-20: 1. When said R is2And (3) mixing the reaction system with water when the reaction system is 2-cyanobenzyl, and performing suction filtration. The volume ratio of the water to the DMSO is preferably 10: 1-20: 1.
In the step (3), it is preferable to include the following steps: dissolving the compound of formula IV in DMF at 20-60 deg.C, and reacting with carbonate of alkali metal and R1And mixing the X and carrying out 1-site nucleophilic substitution reaction. The alkali metal carbonate may be selected from alkali metal carbonates known to those skilled in the art to be suitable for use in the present invention, preferably potassium carbonate. The carbonate of the alkali metal and R1The molar ratio of X is preferably 1.1:1 to 3:1, more preferably 1.1:1 to 2: 1. The amount of DMF is not required to influence the normal reaction, and is preferably 7-15 ml/g of the compound of formula IV. The compound of formula IV and R1The molar ratio of X is preferably 2:1 to 1:1, more preferably 1.5:1 to 1: 1. The reaction temperature is preferably from 25 ℃ to 60 ℃, more preferably from 50 ℃ to 60 ℃. The progress of the nucleophilic substitution reaction at position 1 can be monitored by TLC or HPLC, typically as R1The end point of the reaction is when X disappears. Said nucleophilic substitution reaction at position 1 may be followed by a work-up procedure to further purify the compound of formula iii, which preferably comprises the steps of: mixing the reaction system with water, filtering, dissolving the filter cake with ethyl acetate, washing with saturated saline solution, drying the organic phase with anhydrous sodium sulfate, concentrating, and performing column chromatography. Wherein, the conditions and the operation steps of the column chromatography are selected according to the conditions and the operation steps of the conventional column chromatography in the field.
In the step (4), it is preferable to include the following steps: dissolving the compound shown in the formula III in dichloromethane, mixing with organic amine, dropwise adding a mesylation reagent at 0 ℃ to perform mesylation reaction, wherein the reaction temperature is 0-30 ℃. The organic amine may be selected from those known to those skilled in the art to be suitable for use in the present invention, preferably a tertiary amine. The tertiary amine is preferably triethylamine. The molar ratio of the organic amine to the compound shown in the formula III is preferably 1.1: 1-4: 1, and more preferably 1.1: 1-2: 1. The mesylating agent may be selected from mesylating agents known to those skilled in the art to be suitable for use in the present invention, preferably methanesulfonyl chloride. The molar ratio of the mesylating agent to the compound of formula III is preferably 1.1:1 to 2:1, more preferably 1.1:1 to 1.5: 1. The amount of the dichloromethane is not limited to influence the normal reaction, preferably 2-20 ml/g of the compound shown in the formula III, and more preferably 2-10 ml/g of the compound shown in the formula III. The progress of the mesylation reaction can be monitored by TLC or HPLC, and is generally indicated as the end point of the reaction when the compound of formula III is eliminated. Said mesylation may be followed by a work-up procedure to further purify the compound of formula ii, which preferably comprises the steps of: mixing the reaction system with saturated sodium carbonate, extracting the water phase with dichloromethane, washing the organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography. Wherein, the conditions and the operation steps of the column chromatography are selected according to the conditions and the operation steps of the conventional column chromatography in the field.
The invention also provides any intermediate for preparing the xanthine compound shown in the formula I,
wherein R is1And R2All as described above.
Among said compounds of formula III and formula II, R is preferred1When it is 4-methylquinazolin-2-yl, R2Is but-2-ynyl, R1When it is a naphthalen-1-yl group, R2Is but-2-ynyl, R1When it is a naphthalen-1-yl group, R2Is 2-cyanobenzyl, R1When it is 4-methylquinazolin-2-yl, R2Is 2-cyanobenzyl, R1In the case of 6,7, 8-trifluoro-4- (4-fluorophenylthio) quinolin-3-yl, R2Is but-2-ynyl, or R1In the case of 7-chloro-6-fluoro-4-methoxyquinolin-3-yl, R2Is but-2-ynyl.
The invention also provides application of the xanthine compound shown as the formula I or the pharmaceutically acceptable salt thereof in preparing medicines for treating and/or preventing non-insulin-dependent diabetes mellitus, hyperglycemia or insulin resistance.
The invention also provides application of the xanthine compound shown as the formula I or the pharmaceutically acceptable salt thereof in preparing DPP-4 enzyme activity inhibitors or medicines for treating and/or preventing diseases related to the DPP-4 enzyme through inhibiting the DPP-4 enzyme. Wherein the disease is diabetes and/or hyperglycemia.
A preferred route for preparing compounds of formula I according to the invention is as follows:
the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
Some of the compounds of the present invention are shown in tables 1-5.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the xanthine compound and the salt thereof provide a new direction for the research and development of a novel blood sugar reducing medicament DPP-4 inhibitor, and have important significance for the development of the DPP-4 inhibitor.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples, undefined abbreviations have their commonly accepted meaning, unless otherwise stated, all room temperatures refer to temperatures of 20 ℃ to 30 ℃.
Method example 1
Synthesis of 8-hydroxymethyl-3-methylxanthine (formula V)
Reacting 5, 6-diamino-1-methyl uracil (10g, 64.1mmol) (5, 6-diamino-1-methyl uracil synthesis method see document J.Med.chem.2009,52,6433 one 6446) into water 30mL, adding glycolic acid (4.87g, 128.2mmol), 100 ℃ reaction for 3.5 hours, adding sodium hydroxide (4.3g, 107.5mmol), 100 ℃ reaction for 5 hours, cooling to room temperature to precipitate solid, suction filtration, filter cake with water recrystallization, 6.2g, yield 78.8%. m.p. is more than 250 ℃.1HNMR(ppm，DMSO)：4.33(s,2H)，3.30(s,3H)。
Method example 2
Synthesis of 7- (but-2-ynyl) -8-hydroxymethyl-3-methylxanthine (formula IV)
8-hydroxymethyl-3-methylxanthine (10g, 51.0mmol) was mixed with DMSO70mL, diisopropylethylamine (6.6g, 51.0mmol) was added, 1-bromo-2-butyne (7.8g, 51.0mmol) was added at room temperature, and the mixture was stirred at room temperature for 1.5 hours, after TLC showed disappearance of the starting material, 1300mL of dichloromethane was added to the reaction mixture to precipitate a solid, which was filtered with suction to obtain 10.4g of a white product with a yield of 82.5%. m.p. is more than 250 ℃,1HNMR(ppm，DMSO)：5.13(s,2H)，4.61(d,2H)，3.32(s,3H)，1.76(s,3H)。
method example 3
Synthesis of 7- (2-cyanobenzyl) -8-hydroxymethyl-3-methylxanthine (formula IV)
8-hydroxymethyl-3-methylxanthine (10.0g, 51.0mmol) was mixed with DMSO70mL, diisopropylethylamine (6.6g, 51.0mmol) was added, o-cyanobenzyl chloride (6.8g, 51.0mmol) was added at room temperature, and the mixture was stirred at room temperature for 1.5 hours, after TLC showed disappearance of the starting material, 1000mL of water was added to the reaction solution to precipitate a solid, which was then filtered with suction to obtain 9.1g of a product with a yield of 53.5%. m.p. is more than 250 ℃,1HNMR(ppm，DMSO)：7.85-7.87(m,1H)，7.58-7.62(m,1H)，7.47-7.49(m,1H)，6.92(d,1H)，5.76(s,2H)，4.58(d,2H)，3.38(s,3H)。
method example 4
Synthesis of 1- (4-methylquinazolin-2-yl) methyl-7- (but-2-ynyl) -8-hydroxymethyl-3-methylxanthine (formula III)
7- (but-2-ynyl) -8-hydroxymethyl-3-methylxanthine (5.0g, 20.1mmol) was mixed with DMF50mL, anhydrous potassium carbonate (4.4g, 32.2mmol) and 2-iodomethyl-4-methylquinazoline (5.7g, 16.1mmol) were added and reacted at 50 ℃ for 3 hours, TLC showed disappearance of the starting material, 500mL of water was added, suction filtration was carried out, the cake was dissolved with ethyl acetate, washed with saturated brine 3 times, dried over anhydrous sodium sulfate, concentrated, and column chromatography was carried out to give 3.6g, yield 48.3%. m.p. 106-108 ℃,1HNMR(ppm，DMSO)：8.04(d,1H)，7.87(d,1H)，7.75-7.79(m,1H)，7.52-7.56(m,1H)，5.60(s,2H)，5.26(s,2H)，4.95(d,2H)，3.63(s,3H)，2.92(s,3H)，1.83(s,3H)。
method example 5
Synthesis of 1- (naphthalen-1-ylmethyl) -7- (2-cyanobenzyl) -8-hydroxymethyl-3-methylxanthine (formula III)
7- (2-cyanobenzyl) -8-hydroxymethyl-3-methylxanthine (5.0g, 16.1mmol) was mixed with DMF50mL, anhydrous potassium carbonate (3.6g, 25.8mmol) and 1-chloromethylnaphthalene (2.8g, 16.1mmol) were added, reaction was carried out at 60 ℃ for 3 hours, TLC showed disappearance of the starting material, 500mL of water was added, suction filtration was carried out, the cake was dissolved with ethyl acetate, washed with saturated brine 3 times, dried over anhydrous sodium sulfate, concentrated, and column chromatography was carried out to give 4.4g, yield 61.0%. m.p. 208-210 ℃,1HNMR(ppm，DMSO)：8.22-8.24(m,1H)，7.83-7.86(m,1H)，7.71-7.76(m,2H)，7.44-7.55(m,4H)，7.34-7.38(m,1H)，7.28-7.30(m,1H)，7.06(d,1H)，5.88(s,2H)，5.68(s,2H)，4.71(d,2H)，3.58(s,3H)。
method example 6
Synthesis of 1- [6,7, 8-trifluoro-4- (4-fluorophenylthio) quinolin-3-yl ] methyl-7- (but-2-ynyl) -8-hydroxymethyl-3-methylxanthine (formula III)
7- (but-2-ynyl) -8-hydroxymethyl-3-methylxanthine (5.0g, 20.1mmol) was mixed with DMF50mL, anhydrous potassium carbonate (3.6g, 25.8mmol) and 3-bromomethyl-6, 7, 8-trifluoro-4- (4-fluorophenylthio) quinoline (8.1g, 20.1mmol) were added and reacted at 60 ℃ for 3 hours, TLC showed disappearance of starting material, 500mL of water was added, suction filtered, the filter cake was filtered with acetic acidDissolving in ethyl ester, washing with saturated salt solution for 3 times, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain 8.3g with yield of 65.0%. m.p. 206-208 ℃,1HNMR(ppm，DMSO)：8.85(s,1H)，8.05-8.07(m,1H)，7.15-7.18(m,2H)，7.04-7.09(m,2H)，5.71(s,2H)，5.18(s,2H)，4.67(d,2H)，3.36(s,3H)，1.78(s,3H)。
method example 7
Synthesis of 1- (6-fluoro-7-chloro-4-methoxyquinolin-3 yl) methyl-7- (but-2-ynyl) -8-hydroxymethyl-3-methylxanthine (formula III)
7- (but-2-ynyl) -8-hydroxymethyl-3-methylxanthine (2.36g, 9.5mmol) was mixed with DMF16mL, anhydrous potassium carbonate (2.1g, 15.2mmol) and 3-bromomethyl-6-fluoro-7-chloro-4-methoxyquinoline (2.9g, 9.5mmol) were added and reacted at 60 ℃ for 3 hours, TLC showed disappearance of starting material, 500mL of water was added and filtration was carried out, the filter cake was refluxed with 100mL of ethanol for half an hour and filtration gave 2.19g, 48.9% yield. m.p. 180-182 ℃,1HNMR(ppm，DMSO)：8.66(s,1H)，8.25(d,1H)，8.01(d,2H)，5.31(s,2H)，5.20(d,2H)，4.67(d,2H)，4.06(s,3H)，3.43(s,3H)，1.77(s,3H)。
method example 8
Synthesis of 1- (4-methylquinazolin-2-yl) methyl-7- (but-2-ynyl) -8-methanesulfonyloxymethyl-3-methylxanthine (formula II)
1- (4-methyl quinazoline-2-yl) -methyl 7- (butyl-2-alkynyl) -8-hydroxymethyl-3-methylxanthine (2g, 5.0mmol) and dichloromethane 20mL are mixed, triethylamine (0.8g, 8.0mmol) is added, the temperature is reduced to-5 ℃, methanesulfonyl chloride (0.7g, 6.0mmol) is added dropwise while keeping the temperature at 0 ℃, the reaction is carried out for 2h at 0-5 ℃, TLC shows that the raw material disappears, saturated sodium carbonate is added for layering, dichloromethane is used for 2 times, saturated common salt is washed for 3 times, anhydrous sodium sulfate is dried, concentrated and column chromatography is carried out, so 1.5g is obtained, and the yield is 63.0%. m.p. 182-184 ℃,1HNMR(ppm，CDCl3)：8.04(d,1H)，7.87(d,1H)，7.75-7.79(m,1H)，7.52-7.56(m,1H)，5.57(s,2H)，5.51(s,2H)，5.31(s,2H)，3.61(s,3H)，3.16(s,3H)，2.90(s,3H)，1.82(s,3H)。
method example 9
Synthesis of 1- (naphthalen-1-ylmethyl) -7- (2-cyanobenzyl) -8-methanesulfonyloxymethyl-3-methylxanthine (formula II)
1- (4-methyl-quinazolin-2-yl) -methyl 7- (but-2-ynyl) -8-hydroxymethyl-3-methylxanthine (2g, 4.4mmol) was mixed with 20mL of dichloromethane, triethylamine (0.7g, 7.0mmol) was added, the temperature was reduced to-5 ℃ and 0 ℃ was maintained and methanesulfonyl chloride (0.61g, 5.3mmol) was added dropwise and reacted at 0-5 ℃ for 2h, TLC showed disappearance of the starting material, layering was added with saturated sodium carbonate, extraction was performed with dichloromethane 2 times, washing with saturated brine for 3 times, drying with anhydrous sodium sulfate, concentration and column chromatography gave 1.9g, 81.0% yield. m.p. 204-206 ℃,1HNMR(ppm，CDCl3)：8.22-8.24(m,1H)，7.83-7.86(m,1H)，7.71-7.76(m,2H)，7.44-7.55(m,4H)，7.34-7.38(m,1H)，7.28-7.30(m,1H)，7.06(d,1H)，5.94(s,2H)，5.69(s,2H)，5.26(s,2H)，3.62(s,3H)，3.00(s,3H)。
method example 10
Synthesis of 1- [6,7, 8-trifluoro-4- (4-fluorophenylthio) quinolin-3-yl ] methyl-7- (but-2-ynyl) -8-methanesulfonyloxymethyl-3-methylxanthine (formula II)
Mixing 1- (4-methyl quinazoline-2-yl) -methyl 7- (butyl-2-alkynyl) -8-hydroxymethyl-3-methylxanthine (2g, 3.5mmol) with 20mL of dichloromethane, adding triethylamine (0.56g, 5.6mmol), cooling to-5 ℃, keeping 0 ℃ and dropwise adding methanesulfonyl chloride (0.48g, 4.2mmol), reacting for 2h at 0-5 ℃, TLC shows that the raw material disappears, adding saturated sodium carbonate for layering, extracting with dichloromethane for 2 times, washing with saturated salt water for 3 times, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain 2.2g, the yield is 72.0%. m.p. 150-153 ℃,1HNMR(ppm，CDCl3)：8.78(s,1H)，7.96-8.01(m,1H)，7.05-7.25(m,2H)，6.88-6.93(m,2H)，5.60(s,2H)，5.44(s,2H)，5.24(s,2H)，3.36(s,3H)，3.14(s,3H)，1.82(s,3H)。
method example 11
Synthesis of 1- (6-fluoro-7-chloro-4-methoxyquinolin-3-yl) methyl-7- (but-2-ynyl) -8-methanesulfonyloxymethyl-3-methylxanthine (formula II)
1- (6-fluoro-7-chloro-4-methoxyquinolin-3 yl) methyl-7- (but-2-ynyl) -8-hydroxymethyl-3-methylxanthine (1.89g, 4.0mmol) was mixed with 40mL of dichloromethane, triethylamine (0.65g, 6.4mmol) was added, the temperature was reduced to-5 ℃ and methanesulfonyl chloride (0.55g, 4.8mmol) was added dropwise while maintaining at 0 ℃, the reaction was carried out at 0-5 ℃ for 2 hours, TLC showed disappearance of the starting material, saturated sodium carbonate was added thereto for layering, dichloromethane was extracted 2 times, saturated brine was washed 3 times, dried over anhydrous sodium sulfate, concentrated, and column chromatography gave 1.25g, yield 49.0%. m.p. 170-172 ℃.
Method example 12
Synthesis of 1- (4-methylquinazolin-2-yl) methyl-7- (but-2-ynyl) -8- (R-3-aminopiperidin-1-yl) methyl-3-methylxanthine (I-1)
R-3-tert-Butoxyacylaminopiperidine (136mg, 0.68mmol) and triethylamine (82mg, 0.81mmol) were dissolved in dichloromethane, 1- (4-methylquinazolin-2-yl) -methyl-7- (but-2-ynyl) -8-methanesulfonyloxymethyl-3-methylxanthine (300mg, 0.62mmol) was added at room temperature and reacted for 2h at room temperature, TLC showed complete disappearance of the starting material, water and dichloromethane were added, the organic layer was separated, dried over anhydrous sodium sulfate, concentrated and column chromatographed to give a white solid. The white solid was dissolved in 5mL of dichloromethane, 1.3mL (17.5mmol) of trifluoroacetic acid was added, the reaction was carried out at room temperature for 1.5h, a saturated aqueous solution of sodium carbonate was added to neutralize the trifluoroacetic acid until the aqueous layer became alkaline, dichloromethane was extracted 2 times, saturated brine was washed 3 times, dried over anhydrous sodium sulfate, and concentrated to give 170mg, yield 56.7%. The synthesis methods of the compounds I-8, I-14, I-19 and I-25 are the same as above.
Method example 13
Synthesis of 1- (4-methylquinazolin-2-yl) methyl-7- (but-2-ynyl) -8- (2-aminoethylamino) methyl-3-methylxanthine (I-2)
Ethylenediamine (124mg, 2.07mmol) was dissolved in dichloromethane, 1- (4-methylquinazolin-2-yl) -methyl-7- (but-2-ynyl) -8-methanesulfonyloxymethyl-3-methylxanthine (100mg, 0.21mmol) was added at room temperature, reaction was carried out for 1h, TLC showed disappearance of the starting material, dichloromethane (20 mL) was added, the organic layer was washed 4 times with water, dried over anhydrous sodium sulfate, and concentrated to give 80mg of white color with a yield of 87.0%. The synthesis methods of the compounds I-3, I-4, I-6, I-7, I-9 to I-11, I-15 to I-17, I-20 to I-22, I-26 and I-27 to I-31 are the same as above.
Method example 14
Synthesis of 1- (4-methylquinazolin-2-yl) methyl-7- (but-2-ynyl) -8- (4-aminopiperidin-1-yl) methyl-3-methylxanthine (I-5)
4-Phthalidomide (156mg, 0.68mmol) and triethylamine (82mg, 0.81mmol) were dissolved in 2ml of dichloromethane, 1- (4-methylquinazolin-2-yl) -methyl-7- (but-2-ynyl) -8-methanesulfonyloxymethyl-3-methylxanthine (300mg, 0.62mmol) was added at room temperature, the reaction was carried out at room temperature for 2h, TLC showed complete disappearance of the starting material, water and dichloromethane were added, the organic layer was separated, the aqueous layer was extracted twice with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and column-chromatographed to give a white solid. Dissolving the white solid in dichloromethane 2mL, adding ethanolamine 1.5mL (25mmol), reacting at room temperature for 2h, adding water and dichloromethane, separating organic layer, extracting water layer twice with dichloromethane, combining organic layers, washing with water for 4 times, drying with anhydrous sodium sulfate, and concentrating to obtain 120mg, yield 40.0%. The synthesis methods of the compounds I-12, I-18 and I-23 are the same as above.
Method example 15
Synthesis of 1- (naphthalen-1-ylmethyl) -7- (2-cyanobenzyl) -8-guanidinomethyl-3-methylxanthine (I-13)
Guanidine hydrochloride (153mg, 1.60mmol) and potassium tert-butoxide (358mg, 3.20mmol) were dissolved in tert-butanol, 1- (. alpha. -naphthylmethyl) -7- (2-cyanobenzyl) -8-methanesulfonyloxymethyl-3-methylxanthine (150mg, 0.32mmol) was added and heated to 50 ℃ for reaction for 3h, TLC showed disappearance of the starting material, water and dichloromethane were added, the organic layer was separated, dichloromethane was extracted 2 times, the organic layers were combined, washed 4 times with water, dried over anhydrous sodium sulfate, concentrated, and column chromatographed to give 55mg, 40.0% yield.
Method example 16
Synthesis of 1- (4-methylquinazolin-2-yl) -7- (2-cyanobenzyl) -8-aminomethyl-3-methylxanthine (I-24)
2mL of methylene chloride and 0.5mL of an ethanol solution of 13mol/L ammonia were mixed, 1- (4-methylquinazolin-2-yl) -7- (2-cyanobenzyl) -8-methanesulfonyloxymethyl-3-methylxanthine (100mg, 0.18mmol) was added, and the mixture was stirred at 30 ℃ for 7 hours, whereupon TLC showed the disappearance of the starting material, 20mL of methylene chloride was added, the mixture was washed with water 4 times, dried over anhydrous sodium sulfate, concentrated, recrystallized from 2mL of ethanol, and filtered with suction to obtain 56mg, and the yield was 65.9%. The synthesis method of the compound I-32 is the same as the above.
Method example 17
Synthesis of 1- (naphthalen-1-ylmethyl) -7- (2-cyanobenzyl) -8- (2-aminoethylamino) methyl-3-methylxanthine dihydrochloride hemihydrate (I-15 dihydrochloride hemihydrate)
1- (naphthalen-1-ylmethyl) -7- (2-cyanobenzyl) -8- (2-aminoethylamino) methyl-3-methylxanthine (200mg, 0.4mmol) was dissolved in 4mL of refluxing ethanol and 2mL of methanol, and 2mol/L of an aqueous solution of LHCl (0.4mL, 0.80mmol) was added thereto, followed by refluxing for 30min, followed by cooling to 0 ℃ for crystallization and suction filtration to give 150mg of 1- (naphthalen-1-ylmethyl) -7- (2-cyanobenzyl) -8- (2-aminoethylamino) methyl-3-methylxanthine dihydrochloride hemihydrate in 64.3% yield. mp: decomposing at 188 ℃. Elemental analysis: c: 58.54, H: 5.25, N: 16.83, Cl: 12.04 (theoretical content C: 58.44, H: 5.25, N: 17.04, Cl: 12.32).
Method example 18
Synthesis of 1- (naphthalen-1-ylmethyl) -7- (2-cyanobenzyl) -8- (2-aminoethylamino) methyl-3-methylxanthine phosphate monohydrate (I-15 phosphate monohydrate)
1- (naphthalen-1-ylmethyl) -7- (2-cyanobenzyl) -8- (2-aminoethylamino) methyl-3-methylxanthine (150mg, 0.30mmol) was dissolved in 3mL of refluxing ethanol and 1mL of methanol, 85% phosphoric acid (35mg, 0.30mmol) was added, 2mL of water was added, and after refluxing for 30min, the temperature was lowered to 0 ℃ to crystallize, followed by suction filtration to give 120mg of 1- (naphthalen-1-ylmethyl) -7- (2-cyanobenzyl) -8- (2-aminoethylamino) methyl-3-methylxanthine phosphate monohydrate in a yield of 64.7%. mp: 168 ℃ and 170 ℃. Elemental analysis: c: 55.25, H: 5.29, N: 15.99 (theoretical content C: 55.17, H: 5.29, N: 16.08).
Method example 19
Synthesis of 1- (naphthalen-1-ylmethyl) -7- (2-cyanobenzyl) -8- (2-aminoethylamino) methyl-3-methylxanthine benzoate (I-15 benzoate)
1- (naphthalen-1-ylmethyl) -7- (2-cyanobenzyl) -8- (2-aminoethylamino) methyl-3-methylxanthine (150mg, 0.30mmol) was dissolved in 3mL of refluxing ethanol and 1mL of methanol, benzoic acid (37mg, 0.30mmol) was added thereto, the mixture was refluxed for 30min, then the solvent was concentrated off, 2mL of ethanol was added thereto, the mixture was refluxed and dissolved in ethanol, cooled to 0 ℃ to crystallize, and then subjected to suction filtration to obtain 150mg of 1- (naphthalen-1-ylmethyl) -7- (2-cyanobenzyl) -8- (2-aminoethylamino) methyl-3-methylxanthine benzoate in a yield of 80.2%. mp: 158 deg.c and 160 deg.c,1HNMR(ppm，DMSO)：2.71(t,2H)，2.78(t,2H)，3.47(s,3H)，3.86(s,2H)，5.44(s,2H)，5.78(s,2H)，6.93(t,2H)，7.27-7.33(m,4H)，7.46(t,1H)，7.53(t,2H)，7.61(t,1H)，7.75-7.83(m,4H)，7.90(t,1H)，8.11(t,1H)。
effects of the embodiment
Partial piperazine or 3-aminopiperidine compounds are subjected to in vitro DPP-4 enzyme inhibition test
The DPP-4 enzyme activity determination method is a color development method using glycylproline p-nitroaniline (Gly-Pro-p-nitroanilide) as a substrate. Under the alkaline condition, DPP-4 catalyzes a substrate Gly-Pro-p-nitroanilide to hydrolyze, glycylproline and yellow p-nitroaniline are generated, the p-nitroaniline has a characteristic absorption peak at the wavelength of 405nm, the absorption value measured at the wavelength of 405nm by a spectrophotometer or an enzyme-labeling instrument, namely the generation amount of chromophoric group PNA reflects the activity of enzyme, and the reaction formula is as follows.
The amount of DPP-4 enzyme required for hydrolyzing 1. mu. mol of Gly-Pro-p-nitroanilide in one minute is defined as 1U, various inhibitors with different concentrations are added to a DPP-4 enzyme activity measuring system (substrate 0.4mM, appropriate amount of DPP-4, buffer 50mM Tris-HCl, pH 8.3), the absorbance at 405nm is measured by a spectrophotometer or a microplate reader after reacting for one hour at 37 ℃, and the absorbance measured at 405nm is converted into the amount of p-nitroanilide produced according to Beer-Bouguer's law. For a certain inhibitor, the activity of each inhibitor was evaluated by defining the amount of inhibitor required to inhibit 1U of enzyme activity as one unit of inhibitory activity.
The screening of the inhibitor is to form an enzyme activity determination system by a certain amount of enzyme, add various inhibitors with different amounts and blank reference, and the data in the table 1 shows that part of the compounds in the invention have certain DPP-4 inhibitory activity, thereby playing a guiding role in developing DPP-4 inhibitors with novel structures and structural modification in the future.
Table 1: partial compounds have inhibition rate on DPP-4 enzyme at concentration of 10 mu g/mL
| No. | Inhibition rate | No. | Inhibition rate | No. | Inhibition rate | No. | Inhibition rate |
| I-1 | 77.9 | I-10 | 59.7 | I-17 | 79.0 | I-23 | 43.5 |
| I-2 | 94.3 | I-12 | 47.4 | I-18 | 79.0 | I-25 | 41.0 |
| I-3 | 94.4 | I-14 | 78.9 | I-19 | 53.3 | I-26 | 43.6 |
| I-4 | 69.6 | I-15 | 95.6 | I-20 | 97.0 | ||
| I-9 | 47.4 | I-16 | 68.6 | I-22 | 49.6 |
Claims (22)
1. A xanthine compound shown in formula I or its pharmaceutically acceptable salt,
wherein,
R1is a bicyclic aromatic substituent group as shown in a formula VII; a and B are both C, R4Is H or CH3，R5、R6And R7Is H, said substituent of the formula VII being bonded via the 1-positionThe parent nucleus structures of the compounds of formula I are linked; alternatively, A and B are both N, R4Is H or CH3，R5、R6And R7Is H, the substituent of the formula VII is connected with the mother nucleus structure of the compound of the formula I through the 2 position;
R2is 2-cyanobenzyl or but-2-ynyl;
R3is composed ofn is 2-4, amino, guanidino orm is 2-3, D is H or NH2E is CH2NH or CHNH2；
And when R is1Is a bicyclic aromatic substituent represented by formula VII, wherein A and B are N, R4Is CH3Said substituent of formula VII being attached to the compound of formula I via the 2-position, and said R2When it is 2-cyanobenzyl, then said R3Is composed ofn is 2-4, amino, guanidino orm is 2-3, D is H or NH2E is CH2Or NH.
2. The xanthine compound or pharmaceutically acceptable salt thereof according to claim 1, wherein:
said R1When it is a naphthalen-1-yl group, said R3Is 2-aminoethylamino, 3-aminopropylamino, 4-aminobutylamino, R-3-aminopiperidin-1-yl, piperazin-1-yl, homopiperazin-1-yl or 4-aminopiperidine-1-yl; said R1When it is 4-methylquinazolin-2-yl, R is3Is 2-aminoethylamino, 3-aminopropylamino, 4-aminobutylamino, R-3-aminopiperidin-1-yl, piperazin-1-yl or homopiperazin-1-yl.
3. The xanthine compound or pharmaceutically acceptable salt thereof according to claim 2, wherein: when R is1Is 4-methyl-quinazolin-2-yl and R2When it is but-2-ynyl, R3Is R-3-aminopiperidin-1-yl, 2-aminoethylamino, piperazin-1-yl, homopiperazin-1-yl, 3-aminopropylamino or 4-aminobutylamino;
when R is1Is naphthalen-1-yl and R2When it is but-2-ynyl, R3Is R-3-aminopiperidin-1-yl, 2-aminoethylamino, piperazin-1-yl, homopiperazin-1-yl or 4-aminopiperidin-1-yl;
when R is1Is naphthalen-1-yl and R2In the case of 2-cyanobenzyl, R3Is R-3-aminopiperidin-1-yl, 2-aminoethylamino, piperazin-1-yl, homopiperazin-1-yl or 4-aminopiperidin-1-yl;
when R is1Is 4-methyl-quinazolin-2-yl and R2In the case of 2-cyanobenzyl, R3Is R-3-aminopiperidin-1-yl, 2-aminoethylamino, piperazin-1-yl or homopiperazin-1-yl.
4. The xanthine compound or pharmaceutically acceptable salt thereof according to claim 1, wherein: when R is1Is naphthalen-1-yl and R2When it is but-2-ynyl, R3Is guanidino; when R is1Is 4-methyl-quinazolin-2-yl and R2In the case of 2-cyanobenzyl, R3Is an amino group.
5. The xanthine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: the salt is hydrochloride, sulfate, hydrobromide, acetate, phosphate or benzoate.
6. The xanthine compound or pharmaceutically acceptable salt thereof of claim 5, wherein: the hydrochloride and/or phosphate salt is present in the form of a hydrate.
7. A process for producing the xanthine compound I as claimed in any one of claims 1 to 4,
when said R is3Is composed ofn is 2 to 4, amino group,When m is 2-3, E is NH and D is H, the method comprises the following steps: reacting a compound of formula II with R in a polar aprotic solvent at 20 ℃ to 30 ℃3H, carrying out nucleophilic substitution reaction;
wherein R is1And R2Are as defined in any one of claims 1 to 4;
when said R is3Is composed ofm is 2 and D is NH2And E is CH2When the method is used, the method comprises the following steps: firstly, performing nucleophilic substitution reaction on a compound shown in a formula II and R-3-tert-butoxy acyl amino piperidine in a polar aprotic solvent at the temperature of 20-30 ℃ under the action of tertiary amine, and performing post-treatment on a product subjected to the nucleophilic substitution reaction; secondly, performing tert-butoxy acyl protecting group removing reaction on the post-treated product obtained in the step I to obtain a compound shown in the formula I;
wherein R is1And R2Are as defined in any one of claims 1 to 4;
when said R is3Is composed ofm is 2, D is H and E is CHNH2When the method is used, the method comprises the following steps: firstly, performing nucleophilic substitution reaction on a compound shown in a formula II and 4-phthaloylaminopiperidine in a polar aprotic solvent at the temperature of 20-30 ℃ under the action of tertiary amine, and performing post-treatment on a product after the nucleophilic substitution reaction; secondly, performing phthaloyl protecting group removing reaction on the post-treated product obtained in the step I to obtain a compound shown in the formula I;
wherein R is1And R2Are as defined in any one of claims 1 to 4;
when said R is3When guanidino, it comprises the following steps: performing nucleophilic substitution reaction on guanidine hydrochloride and a compound shown in a formula II in an alcohol solvent at the reaction temperature of 20-60 ℃ under the action of alkali to obtain the compound shown in the formula I;
wherein R is1And R2Are as claimed in any one of claims 1 to 4.
8. The process for producing the xanthine compound I according to claim 7, which comprises:
when said R is3Is composed ofn is 2 to 4, amino group,When m is 2-3, E is NH and D is H, the preparation method of the compound of the formula I comprises the following steps: at 20-30 ℃, R is reacted3Dissolving H in a polar aprotic solvent, mixing with a compound shown in a formula II, and carrying out nucleophilic substitution reaction;
when said R is3When H is ethylenediamine, homopiperazine, 1, 3-propanediamine, 1, 4-butanediamine or piperazine, the molar ratio of H to the compound of the formula II is 2: 1-10: 1; when said R is3When it is amino, R is3H takes part in the reaction in the form of ethanol solution of ammonia; the molar ratio of ammonia to the compound in the formula II in the ammonia ethanol solution is 2: 1-50: 1;
the polar aprotic solvent is dichloromethane;
when R is2When it is but-2-ynyl, R1Is 4-methyl quinazolin-2-yl or naphthalen-1-yl; or when R is2In the case of 2-cyanobenzyl, R1Is 4-methyl quinazoline-2-yl or naphthalene-1-yl.
9. The process for producing the xanthine compound I according to claim 8, which comprises:
when said R is3When H is ethylenediamine, homopiperazine, 1, 3-propanediamine, 1, 4-butanediamine or piperazine, the molar ratio of H to the compound of the formula II is 5: 1-10: 1; when said R is3And when the amino is contained, the molar ratio of ammonia in the ethanol solution of ammonia to the compound shown in the formula II is 2: 1-20: 1.
10. The process for producing the xanthine compound I according to claim 7, which comprises:
when said R is3Is composed ofm is 2 and D is NH2And E is CH2The preparation method of the compound of the formula I comprises the following steps: dissolving R-3-tert-butoxy acyl amino piperidine and tertiary amine in polar aprotic solvent at 20-30 deg.c,adding the compound of the formula II into the mixture to carry out nucleophilic substitution reaction, and carrying out post-treatment on a product after the nucleophilic substitution reaction; dissolving the post-treated product obtained in the step I in a polar aprotic solvent at the temperature of 20-30 ℃, mixing the solution with a reagent for removing the tert-butoxy acyl protecting group, and carrying out the reaction for removing the tert-butoxy acyl protecting group to obtain a compound shown in the formula I;
in the step I, the tertiary amine is triethylamine; the molar ratio of the tertiary amine to the compound of the formula II is 1.1: 1-1.5: 1; the polar aprotic solvent is dichloromethane; the molar ratio of the R-3-tert-butoxy acyl amino piperidine to the compound shown in the formula II is 1.0: 1-1.5: 1; the post-treatment comprises the following steps: mixing the reaction system with dichloromethane and water, separating an organic layer, drying with anhydrous sodium sulfate, and concentrating;
in the second step, the polar aprotic solvent is dichloromethane; the reagent for removing the tert-butoxy acyl protecting group is trifluoroacetic acid; the molar ratio of the tert-butoxy acyl protecting group removing reagent to the compound of the formula II is 5: 1-25: 1.
11. The process for producing the xanthine compound I according to claim 7, which comprises:
when said R is3Is composed ofm is 2, D is H and E is CHNH2The preparation method of the compound of the formula I comprises the following steps: dissolving 4-phthaloylaminopiperidine and tertiary amine in a polar aprotic solvent at 20-30 ℃, adding the mixture into a compound in a formula II to perform nucleophilic substitution reaction, and performing post-treatment on a product after the nucleophilic substitution reaction; dissolving the post-treated product obtained in the step I in a polar aprotic solvent at the temperature of 20-30 ℃, mixing the solution with a phthaloyl protecting group removing reagent, and performing a phthaloyl protecting group removing reaction to obtain a compound shown in the formula I;
in the step I, the tertiary amine is triethylamine; the molar ratio of the tertiary amine to the compound of the formula II is 1.1: 1-1.5: 1; the polar aprotic solvent is dichloromethane; the molar ratio of the 4-phthaloylaminopiperidine to the compound of the formula II is 1.0: 1-1.5: 1; the post-treatment comprises the following steps: mixing the reaction system with water and dichloromethane, separating organic layer, extracting water layer with dichloromethane, mixing organic layers, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography;
in the second step, the polar aprotic solvent is dichloromethane; the reagent for removing the phthaloyl protecting group is ethanolamine; the molar ratio of the phthaloyl protective group removing reagent to the compound in the formula II is 2: 1-40: 1.
12. The process for producing the xanthine compound i according to claim 11, which comprises: in the step II, the molar ratio of the phthaloyl protective group removing reagent to the compound in the formula II is 2: 1-20: 1.
13. The process for producing the xanthine compound I according to claim 7, which comprises:
when said R is3In the case of guanidino, the process for the preparation of said compounds of formula I comprises the following steps: dissolving guanidine hydrochloride and alkali in an alcohol solvent at the reaction temperature of 20-60 ℃, and adding a compound shown in a formula II to perform nucleophilic substitution reaction to obtain a compound shown in a formula I;
the alkali is alkali metal compound of alcohol; the alkali metal compound of the alcohol is sodium tert-butoxide or potassium tert-butoxide; the molar ratio of the alkali to the compound of the formula II is 1: 1-10: 1; the alcohol solvent is tert-butyl alcohol; the molar ratio of the guanidine hydrochloride to the compound shown in the formula II is 1: 1-5: 1; the reaction temperature is 40-60 ℃.
14. The process for producing the xanthine compound i according to claim 13, which comprises: the molar ratio of the alkali to the compound of the formula II is 1: 1-5: 1; the molar ratio of the guanidine hydrochloride to the compound shown in the formula II is 1: 1-3: 1.
15. The process for producing the xanthine compound I according to claim 7, which comprises: the compound of the formula II is prepared by the following method:
(1) taking water as a solvent, and carrying out condensation reaction on a compound shown in a formula VI and hydroxyacetic acid under the action of hydroxide of alkali metal, wherein the reaction temperature is 20-100 ℃;
(2) taking DMSO as a solvent, and reacting the compound of the formula V with R under the action of organic amine2Carrying out 7-site nucleophilic substitution reaction on the X to obtain a compound shown in a formula IV, wherein the reaction temperature is 20-30 ℃;
(3) taking DMF as a solvent, and reacting a compound shown in the formula IV with R under the action of carbonate of alkali metal1CH2Carrying out 1-site nucleophilic substitution reaction on the X to obtain a compound shown in a formula III, wherein the reaction temperature is 20-60 ℃;
(4) taking dichloromethane as a solvent, and carrying out mesylation reaction on a compound shown in a formula III and a mesylation reagent under the action of organic amine to obtain a compound shown in a formula II, wherein the reaction temperature is 0-30 ℃;
wherein, R is1And R2Are as defined in any one of claims 1 to 4; x is Cl, Br, I.
16. The process for producing the xanthine compound i according to claim 15, wherein:
the step (1) comprises the following steps: dissolving the compound shown in the formula VI in water at the temperature of 20-100 ℃, mixing the mixture with glycolic acid, reacting for 0.5-2 hours, mixing with hydroxide of alkali metal, and carrying out condensation reaction; the hydroxide of the alkali metal is sodium hydroxide; the hydroxide of the alkali metal participates in the reaction in the form of aqueous solution; the concentration of the alkali metal hydroxide aqueous solution is 3.0-4.5 mol/L; the molar ratio of the alkali metal hydroxide to the compound shown in the formula VI is 1.1: 1-3: 1; the molar ratio of the glycolic acid to the compound shown in the formula VI is 2: 1-4: 1;
the step (2) comprises the following steps: dissolving the compound of formula V in DMSO at 20-30 deg.C, mixing with organic amine, adding R2Carrying out 7-site nucleophilic substitution reaction on the X to obtain a compound shown in the formula IV; the organic amine is diisopropylethylamine; the molar ratio of the organic amine to the compound of the formula V is 1: 1-2: 1; the compound of the formula V and R2The molar ratio of X is 1: 1-2: 1;
in the step (3), the method comprises the following steps: dissolving the compound of formula IV in DMF at 20-60 deg.C, and reacting with carbonate of alkali metal and R1CH2Mixing X, and carrying out 1-site nucleophilic substitution reaction; the carbonate of the alkali metal is potassium carbonate; the carbonate of the alkali metal and R1CH2The molar ratio of X is 1.1: 1-3: 1; the compound of formula IV and R1CH2The molar ratio of X is 2: 1-1: 1;
in the step (4), the method comprises the following steps: dissolving a compound shown in the formula III in dichloromethane, mixing the dichloromethane with organic amine, dropwise adding a mesylation reagent at 0 ℃ to perform mesylation reaction, wherein the reaction temperature is 0-30 ℃; the organic amine is tertiary amine; the tertiary amine is triethylamine; the molar ratio of the organic amine to the compound shown in the formula III is 1.1: 1-4: 1; the mesylation reagent is methanesulfonyl chloride; the molar ratio of the mesylation reagent to the compound shown in the formula III is 1.1: 1-2: 1.
17. The process for preparing the xanthine compound i according to claim 16, wherein:
in the step (1), the concentration of the alkali metal hydroxide aqueous solution is 3.5-4.0 mol/L; the molar ratio of the alkali metal hydroxide to the compound shown in the formula VI is 1.5: 1-2: 1; the molar ratio of the glycolic acid to the compound shown in the formula VI is 2: 1-3: 1; the reaction temperature is 50-100 ℃;
in the step (3), the carbonate of the alkali metal and R1CH2The molar ratio of X is 1.1: 1-2: 1; the compound of formula IV and R1CH2The molar ratio of X is 1.5: 1-1: 1; the reaction temperature is 25-60 ℃;
in the step (4), the molar ratio of the organic amine to the compound shown in the formula III is 1.1: 1-2: 1; the molar ratio of the mesylation reagent to the compound shown in the formula III is 1.1: 1-1.5: 1.
18. The process for preparing the xanthine compound i as claimed in claim 17, wherein: in the step (1), the reaction temperature is 80-100 ℃; in the step (3), the reaction temperature is 50-60 ℃.
19. An intermediate for preparing the xanthine compound I as defined in any one of claims 1 to 4,
wherein R is1And R2The method according to any one of claims 1 to 4.
20. The intermediate according to claim 19 for the preparation of xanthine compound i:
when R is1When it is 4-methylquinazolin-2-yl, R2Is but-2-ynyl;
when R is1When it is a naphthalen-1-yl group, R2Is but-2-ynyl;
when R is1When it is a naphthalen-1-yl group, R2Is 2-cyanobenzyl;
or when R is1When it is 4-methylquinazolin-2-yl, R2Is 2-cyanobenzyl.
21. The use of the xanthine compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, for the preparation of a medicament for the treatment and/or prevention of non-insulin dependent diabetes, hyperglycemia, or insulin resistance.
22. The use of the xanthine compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for preparing a DPP-4 enzyme activity inhibitor or a medicament for treating and/or preventing diseases related thereto by inhibiting DPP-4 enzyme.
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| CN101784278A (en) * | 2007-08-17 | 2010-07-21 | 贝林格尔.英格海姆国际有限公司 | Purin derivatives for use in the treatment of FAB-related diseases |
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| CN1675212A (en) * | 2002-08-21 | 2005-09-28 | 贝林格尔英格海姆法玛两合公司 | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
| CN101784278A (en) * | 2007-08-17 | 2010-07-21 | 贝林格尔.英格海姆国际有限公司 | Purin derivatives for use in the treatment of FAB-related diseases |
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