CN105906580B - Thioproline derivative and its preparation method and application - Google Patents
Thioproline derivative and its preparation method and application Download PDFInfo
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- CN105906580B CN105906580B CN201610326799.2A CN201610326799A CN105906580B CN 105906580 B CN105906580 B CN 105906580B CN 201610326799 A CN201610326799 A CN 201610326799A CN 105906580 B CN105906580 B CN 105906580B
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- DZLNHFMRPBPULJ-VKHMYHEASA-N L-thioproline Chemical class OC(=O)[C@@H]1CSCN1 DZLNHFMRPBPULJ-VKHMYHEASA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 15
- BPMFZUMJYQTVII-UHFFFAOYSA-N guanidinoacetic acid Chemical compound NC(=N)NCC(O)=O BPMFZUMJYQTVII-UHFFFAOYSA-N 0.000 claims description 13
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 11
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 7
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims description 5
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 5
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical group NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 claims description 3
- 229960002134 butafosfan Drugs 0.000 claims description 3
- YHLWPOLSPCBOPC-UHFFFAOYSA-O butyl(2-phosphopropan-2-yl)azanium Chemical group CCCCNC(C)(C)[P+](O)=O YHLWPOLSPCBOPC-UHFFFAOYSA-O 0.000 claims description 3
- 150000002460 imidazoles Chemical class 0.000 claims description 3
- 230000036737 immune function Effects 0.000 claims description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- 150000003147 proline derivatives Chemical class 0.000 claims 1
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 20
- 241000700159 Rattus Species 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- FJWNZTPXVSWUKF-LURJTMIESA-N (4r)-3-[(2-methylpropan-2-yl)oxycarbonyl]-1,3-thiazolidine-4-carboxylic acid Chemical class CC(C)(C)OC(=O)N1CSC[C@H]1C(O)=O FJWNZTPXVSWUKF-LURJTMIESA-N 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000012452 mother liquor Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- -1 formamidine acetate Glycocyamine Chemical group 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 210000003743 erythrocyte Anatomy 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241000287828 Gallus gallus Species 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 210000002540 macrophage Anatomy 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000013067 intermediate product Substances 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000003304 gavage Methods 0.000 description 4
- 230000000242 pagocytic effect Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 210000000952 spleen Anatomy 0.000 description 4
- 206010057249 Phagocytosis Diseases 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 210000003024 peritoneal macrophage Anatomy 0.000 description 3
- 230000008782 phagocytosis Effects 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 210000004988 splenocyte Anatomy 0.000 description 3
- ZONXBXMWKSOXCA-UHFFFAOYSA-N 2-sulfanylpyrrolidine-2-carboxylic acid Chemical class OC(=O)C1(S)CCCN1 ZONXBXMWKSOXCA-UHFFFAOYSA-N 0.000 description 2
- HIDJWBGOQFTDLU-UHFFFAOYSA-N 4-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical class CC(C)(C)OC(=O)NCCCC(O)=O HIDJWBGOQFTDLU-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000002027 dichloromethane extract Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- KVQGGLZHHFGHPU-UHFFFAOYSA-N methyl 4-aminobutanoate Chemical class COC(=O)CCCN KVQGGLZHHFGHPU-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- MMRIIHZNUARDOC-VIFPVBQESA-N CCCN([C@@H](CCO)C(=O)O)C(=O)OC(C)(C)C Chemical compound CCCN([C@@H](CCO)C(=O)O)C(=O)OC(C)(C)C MMRIIHZNUARDOC-VIFPVBQESA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000011938 amidation process Methods 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 235000015177 dried meat Nutrition 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 230000002070 germicidal effect Effects 0.000 description 1
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 230000004727 humoral immunity Effects 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- LWYXLXAMDLNBFQ-UHFFFAOYSA-N iso-6-Carnavalin Natural products CC(O)CCCCCCCCCCC1CCC(O)C(C)N1 LWYXLXAMDLNBFQ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- KAHVZNKZQFSBFW-UHFFFAOYSA-N n-methyl-n-trimethylsilylmethanamine Chemical compound CN(C)[Si](C)(C)C KAHVZNKZQFSBFW-UHFFFAOYSA-N 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000003393 splenic effect Effects 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical class ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical compound OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6539—Five-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of Thioproline derivatives and its preparation method and application, belong to medicinal chemistry art.A kind of Thioproline derivative has general formula (A)Or (B)The structure, wherein, R1 is representedWithIn one kind；R2 is representedWith
Description
Technical field
The present invention relates to a kind of Thioproline derivatives and its preparation method and application, belong to medicinal chemistry art.
Background technology
Thioproline is artificial synthesized for the first time in nineteen thirty-seven, clinically using wide, once for anti-precocious aging, anti-
It is hypertension, antitumor；In terms of animal, there is anti-zoopery Arrhythmia.1980, Spain scientist had found
Thioproline can make the cancerous cell transformation of tissue cultures, revert to normal cell, and keep by the effect to cell membrane
Normal growth.Thioproline clinical medicine is known as Norgamen, is mainly used for treatment head and neck squamous cell carcinoma and works well；
Intramuscular injection has certain mitigation to oophoroma, breast cancer, kidney and thyroid cancer.In addition, Thioproline has transaminase lowering work
With the treatment available for hepatitis, fatty liver.
Therefore, Thioproline is carried out it is appropriate change structure, its biological activity may be remarkably reinforced, to improve later
Clinical efficacy plays the pharmacological action of bigger.
Invention content
The purpose of the present invention is using Thioproline as substrate, being modified with amino acid, there is good pharmacology to obtain
The Thioproline derivative of activity simultaneously provides preparation method and use.
Technical solution provided by the present invention is as follows：
A kind of Thioproline derivative has the following general formula (A) or (B) described structure：
Wherein, R1 is represented
In one kind；R2 is representedIn one kind.
A kind of preparation method of the Thioproline derivative：
General formula (A) compound be with Rx andFor Material synthesis, wherein, Rx represents formamidine acetate
GlycocyamineButafosfanγ-aminobutyric acidImidazolesAnd benzimidazoleIn one kind；
General formula (B) compound be with Ry andFor Material synthesis, wherein, Ry represents glycocyamine, fourth ammonia third
One kind in phosphorus and γ-aminobutyric acid.
Preferably, reaction is the presence in DCC (dicyclohexylcarbodiimide) and DMAP (N, N- dimethyl -4- pyridines amine)
Lower progress, and reaction dissolvent is dichloromethane.
Specific reaction route is as follows：
A kind of purposes of Thioproline derivative in the drug for adjusting immune function is prepared.
Present invention Thioproline derivative as obtained by carrying out changing structure to Thioproline has good pharmacological activity, no
Only there is important academic significance to be also with a wide range of applications.
Specific embodiment
By the following examples to the present invention to further illustrating：
The Thioproline derivant structure formula is as follows：
Embodiment 1：The preparation of compound A-1
0.1mol Thioprolines are dissolved in the NaOH solution of 0.1mol by method known in the field, are added in
1.2mol Boc2After O protects the-NH of Thioproline, then with formamidine acetate carry out amidation process.By gained N-
Boc- Thioprolines are dissolved in 30mL dichloromethane, and 15mmol DCC (dicyclohexylcarbodiimide) are added under condition of ice bath
With 0.5mmol DMAP (N, TMSDMA N dimethylamine yl pyridines), stir 10 minutes, then by 0.12mol formamidine acetates and 0.12mol tri-
Ethamine is dissolved in 15mL dichloromethane, is added dropwise in above-mentioned reaction solution, and drop finishes, and is warmed to room temperature, and is stirred 20 hours, is stopped anti-
Should, 20mL water, layering are added in, dichloromethane extracts, merging organic phase, anhydrous sodium sulfate drying, filtering, and mother liquor is cooled to 0 degree,
0.15mol trifluoroacetic acids are added in, after stirring 3 hours, evaporated under reduced pressure, column chromatography for separation obtains A-1, yield 50%.
MS：m/z 370[M+H]+.1H NMR(400MHz,DMSO-d6):δ=6.78 (m, 1H), 5.03-5.21 (m, 1H),
4.53-4.82(m,1H),3.62(d,2H)1.90(m,2H)ppm.13C NMR(400MHz,DMSO-d6):δ=176.4,
158.0,74.6,61.2,38.5ppm。
Embodiment 2：The preparation of compound A-2
Using 1 gained intermediate product N-Boc- Thioprolines of embodiment as substrate, and by glycocyamine according to this field public affairs
The p- COOH of method known is protected, after forming glycocyamine methyl esters, then it is anti-with the progress amidation of N-Boc- Thioprolines
It should.Specific route is as follows：
- COOH guard methods well known in the art are：10mmol glycocyamines are dissolved in 30ml methanol, at 0 DEG C, are delayed
It is slow to add in 1.2mL thionyl chlorides, after stirring 1 hour, restore room temperature, continue stirring 12 hours, stop reaction, methanol is removed under reduced pressure
Afterwards, 30mL dichloromethane and 0.8mL triethylamines are added in, after being stirred at room temperature 15 minutes, sequentially adds the thio dried meat of 10mmol N-Boc-
Propylhomoserin, 15mmol DCC (dicyclohexylcarbodiimide) and 0.5mmol DMAP (N, N- dimethyl -4- pyridines amine), are stirred at room temperature
20 hours, 30mL water, layering were added in after completion of the reaction, dichloromethane extraction merges organic phase, and anhydrous sodium sulfate is dried, filtering,
Mother liquor is cooled to 0 degree, 0.15mol trifluoroacetic acids removing Boc protecting groups is added in, then again with 1N sodium hydroxide hydrolysis methyl esters, column
Chromatography obtains A-2, yield 55%.
Embodiment 3：The preparation of compound A-3
It is synthesized using 1 gained intermediate product N-Boc- Thioprolines of embodiment as substrate, specific route is as follows：
N-Boc- Thioprolines and each 10mmol of Butafosfan acid are dissolved into 30mL dichloromethane, in condition of ice bath
Lower stirring 10 minutes, then sequentially adds 15mmol DCC (dicyclohexylcarbodiimide) and 0.5mmol DMAP (N, N- diformazans
Base -4- pyridines amine), it is stirred at room temperature 20 hours, adds in 30mL water, layering after completion of the reaction, dichloromethane extraction merges organic
Phase, anhydrous sodium sulfate drying, filtering, mother liquor are cooled to 0 degree, add in 0.15mol trifluoroacetic acids removing Boc protecting groups, column chromatography
Separation, obtains A-3, yield 56%.
Embodiment 4：The preparation of compound A-4
Using 1 gained intermediate product N-Boc- Thioprolines of embodiment as substrate, and by γ-aminobutyric acid according to embodiment
2 methods carry out carboxy protective, and products therefrom γ-aminobutyric acid methyl esters is carrying out synthetic reaction, and specific route is as follows：
Gained γ-aminobutyric acid methyl esters and each 10mmol of N-Boc- Thioprolines are dissolved into 30mL dichloromethane.
It is stirred 10 minutes under condition of ice bath, then sequentially adds 15mmol DCC (dicyclohexylcarbodiimide) and 0.5mmol DMAP
(N, N- dimethyl -4- pyridines amine) is stirred at room temperature 20 hours, adds in 30mL water, layering after completion of the reaction, and dichloromethane extracts,
Merge organic phase, anhydrous sodium sulfate drying is filtered, and mother liquor is cooled to 0 degree, adds in the removing Boc protections of 0.15mol trifluoroacetic acids
Base, then uses 1N sodium hydroxide hydrolysis methyl esters again, and column chromatography for separation obtains A-4, yield 65%.
Embodiment 5：The preparation of compound A-5
Using 1 gained intermediate product N-Boc- Thioprolines of embodiment as substrate, synthetic reaction, specific road are carried out with imidazoles
Line is as follows：
Imidazoles and each 10mmol of N-Boc- Thioprolines are dissolved into 30mL dichloromethane.It is stirred under condition of ice bath
10 minutes, then sequentially add 15mmol DCC (dicyclohexylcarbodiimide) and 0.5mmol DMAP (N, N- dimethyl -4- pyrroles
Pyridine amine), it is stirred at room temperature 20 hours, adds in 30mL water, layering after completion of the reaction, dichloromethane extraction merges organic phase, anhydrous sulphur
Sour sodium drying, filtering, mother liquor are cooled to 0 degree, add in 0.15mol trifluoroacetic acids removing Boc protecting groups, and column chromatography for separation obtains A-
5, yield 30%.
Embodiment 6：The preparation of compound A-6
Using 1 gained intermediate product N-Boc- Thioprolines of embodiment as substrate, synthetic reaction, tool are carried out with benzimidazole
Body route is as follows：
Benzimidazole and each 10mmol of N-Boc- Thioprolines are dissolved into 30mL dichloromethane.Under condition of ice bath
Stirring 10 minutes, then sequentially add 15mmol DCC (dicyclohexylcarbodiimide) and 0.5mmol DMAP (N, N- dimethyl-
4- pyridines amine), it is stirred at room temperature 20 hours, adds in 30mL water, layering after completion of the reaction, dichloromethane extraction merges organic phase, nothing
Aqueous sodium persulfate is dried, and filtering, mother liquor is cooled to 0 degree, adds in 0.15mol trifluoroacetic acids removing Boc protecting groups, column chromatography for separation,
Obtain A-6, yield 32%.
Embodiment 7：The preparation of compound B-1
According to-COOH guard methods described in the embodiment of the present invention 2 ,-the COOH on thio first propylhomoserin is protected with methanol
Shield forms Thioproline methyl esters, as substrate, is then condensed with glycocyamine, specific route is as follows：
Thioproline methyl esters and each 10mmol of glycocyamine are dissolved into 30mL dichloromethane.It is stirred under condition of ice bath
It mixes 10 minutes, then sequentially adds 15mmol DCC (dicyclohexylcarbodiimide) and 0.5mmol DMAP (N, N- dimethyl -4-
Pyridine amine), it is stirred at room temperature 20 hours, adds in 30mL water, layering after completion of the reaction, dichloromethane extraction merges organic phase, anhydrous
Sodium sulphate is dried, and filtering, mother liquor is cooled to 0 degree, and with 1N sodium hydroxide hydrolysis methyl esters, column chromatography for separation obtains B-1, yield 43%.
Embodiment 8：The preparation of compound B-2
With 7 gained Thioproline methyl esters of embodiment, as substrate.According to 1 the method for the embodiment of the present invention, use
Bco2O protects the amino on Butafosfan acid, N-Boc- Butafosfans acid is formed, as substrate and Thioproline first
Ester is synthesized, and specific route is as follows：
Thioproline methyl esters and each 10mmol of N-Boc- Butafosfans acid are dissolved into 30mL dichloromethane.In ice bath
Under the conditions of stir 10 minutes, then sequentially add 15mmol DCC (dicyclohexylcarbodiimide) and 0.5mmol DMAP (N, N-
Dimethyl -4- pyridines amine), it is stirred at room temperature 20 hours, adds in 30mL water, layering after completion of the reaction, dichloromethane extraction is associated with
Machine phase, anhydrous sodium sulfate drying, filtering, mother liquor are cooled to 0 degree, first add in 0.15mol trifluoroacetic acids removing Boc protecting groups, so
1N sodium hydroxide hydrolysis methyl esters is used afterwards, and column chromatography for separation obtains B-2, yield 32%.
Embodiment 9：The preparation of compound B-3
With 7 gained Thioproline methyl esters of embodiment, as substrate.According to 1 the method for the embodiment of the present invention, use
Bco2O protects the amino of γ-aminobutyric acid, N-Boc- γ-aminobutyric acids is formed, as substrate and Thioproline first
Ester is synthesized, and specific route is as follows：
Thioproline methyl esters and each 10mmol of N-Boc- γ-aminobutyric acids are dissolved into 30mL dichloromethane.In ice
Stirred 10 minutes under the conditions of bath, then sequentially add 15mmol DCC (dicyclohexylcarbodiimide) and 0.5mmol DMAP (N,
N- dimethyl -4- pyridines amine), it is stirred at room temperature 20 hours, adds in 30mL water, layering after completion of the reaction, dichloromethane extraction merges
Organic phase, anhydrous sodium sulfate drying, filtering, mother liquor are cooled to 0 degree, first add in 0.15mol trifluoroacetic acids removing Boc protecting groups,
Then 1N sodium hydroxide hydrolysis methyl esters is used, column chromatography for separation obtains B-3, yield 56%.
Embodiment 10：Thioproline derivative is to the adjustment effect of immune functions of rats
(1) SD mouse, male, weight 180-220g, purchased from Shanghai Slac Experimental Animal Co., Ltd., (animal is permitted
Demonstrate,prove SCXK2003-0003), it is divided into 10 groups, every group 10；Sub-cage rearing, cage 1-10.Wherein No. 1 cage, gavage DMSO
1ml once a day, is used in conjunction 3 days；2-7 cages rat distinguishes gavage compound A-1 to A-6；8-10 cages rat distinguishes gavage chemical combination
Object B-1 to B-3.All compound dosages are 10mg/kg weight, are dissolved in gavage in DMSO, once a day, are used in conjunction 3 days.
(2) Germicidal efficacy index
2.1 rat spleen lymphocytes proliferation tests
It after SD rats feed 6 days, weighs, cervical dislocation is put to death.It is sterile to take spleen, prepare splenocyte suspension, canavaline thorn
Splenic lymphocytes differentiation and proliferation is swashed, using MTT colorimetric method for determining spleen lymphocyte proliferation abilities.
2.2NK cytoactive detection
It after SD rats feed 6 days, weighs, cervical dislocation is put to death.It is sterile to take spleen, splenocyte suspension is prepared, with rat T cells
Knurl is target cell, and NK cell activity is measured with lactic dehydrogenase enzyme process.
2.3 antibody-producting cell levels detect
After SD rats feed 6 days, per mouse, the sheep red blood cell (SRBC) suspension of intraperitoneal injection 2% is immunized.After 4 days immune
Extremely, splenocyte suspension is prepared, hemolysis plaque number is counted by Jerne improves slide methods.
The phagocytosis chicken red blood cell experiment of 2.4 rat peritoneal macrophages
After SD rats feed 60 days, per mouse after the chicken erythrocyte suspension 1ml, 30min of intraperitoneal injection 20%, at cervical dislocation
Extremely.Rat faces upward position and fixes, intraperitoneal injection of saline 2ml, rotates mouse plate 1min, and abdominal cavity washing lotion 1ml is sucked out, and point drop is in 2 loads
On slide, after 37 DEG C are incubated 30min, acetone methanol solution (1：1) fixed, 4%Giemsa- phosphate buffers dyeing 3min steams
Distilled water rinsing is dried, read tablet, counts macrophage, the chicken red blood cell number for swallowing the number of macrophages of chicken red blood cell and being swallowed,
It is calculated as follows.
Percentage phagocytosis (%)=(number of macrophages/number of macrophages of phagocytosis chicken red blood cell) × 100%
Chicken red blood cell/the number of macrophages for phagocytic index=swallowed
(3) experimental result
Influence result of the 3.1 Thioproline derivatives to rat immune cells
Influence (n=10) of the 1 Thioproline derivative of table to rat immune cells
Note：(1) subscript " a " represents medicine group compared with the control group, difference extremely significantly (p<0.01)；
(2) subscript " b " represents medicine group compared with the control group, significant difference (p<0.05).
Thioproline derivative can improve the ability and activity level of these immunocytes of rat as shown in Table 1；
Compared with the control group, significant effect (p<0.01 or p<0.05).
Influence result of the 3.2 Thioproline derivatives to rat peritoneal macrophages phagocytic function
Influence (n=10) of the 2 Thioproline derivative of table to rat peritoneal macrophages phagocytic function
Note：(1) subscript " a " represents medicine group compared with the control group, difference extremely significantly (p<0.01)；
(2) subscript " b " represents medicine group compared with the control group, significant difference (p<0.05).
Thioproline derivative can effectively improve the phagocytic activity of the macrophage of rat as shown in Table 2；With compareing
Group is compared, significant effect (p<0.01 or p<0.05).
(4) experiment conclusion
Thioproline derivative can be effectively improved the humoral immunity and cellular immune level of rat.
Claims (4)
1. a kind of Thioproline derivative, which is characterized in that there is the following general formula (A) or (B) described structure：
Wherein, R1 is representedIn one kind；R2 is representedIn one kind.
2. a kind of preparation method of Thioproline derivative, which is characterized in that the Thioproline derivative has following
General formula (A) or (B) described structure：
Wherein, R1 is representedIn one
Kind；R2 is representedIn one kind；
General formula (A) compound be with Rx andFor Material synthesis, wherein, Rx represents formamidine acetate, glycocyamine, fourth
The third phosphorus of ammonia, γ-aminobutyric acid, one kind in imidazoles and benzimidazole；
General formula (B) compound be with Ry andFor Material synthesis, wherein, Ry represents glycocyamine, Butafosfan and
One kind in γ-aminobutyric acid.
3. the preparation method of Thioproline derivative according to claim 2, which is characterized in that reaction be in DCC and
It is carried out in the presence of DMAP, and reaction dissolvent is dichloromethane.
A kind of 4. purposes of Thioproline derivative in the drug for adjusting immune function is prepared, which is characterized in that the sulphur
There is the following general formula (A) or (B) described structure for proline derivative：
Wherein, R1 is representedIn one
Kind；R2 is representedIn one kind.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004004661A2 (en) * | 2002-07-09 | 2004-01-15 | Point Therapeutics, Inc. | Boroproline compound combination therapy |
| CN103204824A (en) * | 2012-01-12 | 2013-07-17 | 清华大学深圳研究生院 | 2-aminothiazole-4-amide derivative, its preparation method and application |
| CN105906601A (en) * | 2016-05-17 | 2016-08-31 | 施维雅(青岛)生物制药有限公司 | Calycosin derivative as well as preparation method and application thereof |
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2016
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004004661A2 (en) * | 2002-07-09 | 2004-01-15 | Point Therapeutics, Inc. | Boroproline compound combination therapy |
| CN103204824A (en) * | 2012-01-12 | 2013-07-17 | 清华大学深圳研究生院 | 2-aminothiazole-4-amide derivative, its preparation method and application |
| CN105906601A (en) * | 2016-05-17 | 2016-08-31 | 施维雅(青岛)生物制药有限公司 | Calycosin derivative as well as preparation method and application thereof |
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