CN115181100A - Sulfonamide micromolecule inhibitor with purine and pyrrolopyrimidine parent nucleus - Google Patents
Sulfonamide micromolecule inhibitor with purine and pyrrolopyrimidine parent nucleus Download PDFInfo
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- CN115181100A CN115181100A CN202210895371.5A CN202210895371A CN115181100A CN 115181100 A CN115181100 A CN 115181100A CN 202210895371 A CN202210895371 A CN 202210895371A CN 115181100 A CN115181100 A CN 115181100A
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- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 239000003112 inhibitor Substances 0.000 title claims abstract description 30
- 229940124530 sulfonamide Drugs 0.000 title claims abstract description 18
- KDOPAZIWBAHVJB-UHFFFAOYSA-N 5h-pyrrolo[3,2-d]pyrimidine Chemical compound C1=NC=C2NC=CC2=N1 KDOPAZIWBAHVJB-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 150000003456 sulfonamides Chemical class 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 150000003384 small molecules Chemical class 0.000 claims abstract description 14
- GHXBPCSSQOKKGB-UHFFFAOYSA-N 2,4-dichloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC(Cl)=C2C=CNC2=N1 GHXBPCSSQOKKGB-UHFFFAOYSA-N 0.000 claims abstract description 7
- RMFWVOLULURGJI-UHFFFAOYSA-N 2,6-dichloro-7h-purine Chemical compound ClC1=NC(Cl)=C2NC=NC2=N1 RMFWVOLULURGJI-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 36
- -1 p-benzylbromobenzenesulfonyl chloride Chemical compound 0.000 claims description 26
- 239000012043 crude product Substances 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 20
- 238000005303 weighing Methods 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 18
- 239000000741 silica gel Substances 0.000 claims description 18
- 229910002027 silica gel Inorganic materials 0.000 claims description 18
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- 238000004440 column chromatography Methods 0.000 claims description 12
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 12
- 239000000843 powder Substances 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 9
- 150000004944 pyrrolopyrimidines Chemical class 0.000 claims description 7
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 238000001514 detection method Methods 0.000 claims description 4
- 238000012544 monitoring process Methods 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 abstract description 19
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 abstract description 19
- 230000000694 effects Effects 0.000 abstract description 15
- 238000013461 design Methods 0.000 abstract description 3
- 125000000565 sulfonamide group Chemical group 0.000 abstract description 3
- 201000011510 cancer Diseases 0.000 description 5
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 4
- 108091007960 PI3Ks Proteins 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- KHBQMWCZKVMBLN-IDEBNGHGSA-N benzenesulfonamide Chemical group NS(=O)(=O)[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 KHBQMWCZKVMBLN-IDEBNGHGSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000009096 changqing Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- DWJMBQYORXLGAE-UHFFFAOYSA-N pyridine-2-sulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=N1 DWJMBQYORXLGAE-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a sulfonamide micromolecule inhibitor taking purine and pyrrolopyrimidine parent nucleus, belongs to the technical field of sulfonamide micromolecule inhibitors, and is characterized in that 2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine and 2, 6-dichloropurine are selected as parent nucleus, and sulfonamide groups are introduced as active groups, so that a series of compound designs are performed. And 30 brand new compounds were synthesized. The activity of A549 cells is tested, and the activity of three compounds reaches below 10 mu M, so that the compounds are expected to be further researched and become small molecule inhibitors which effectively target mTOR targets.
Description
Technical Field
The invention belongs to the technical field of sulfonamide micromolecule inhibitors, and particularly relates to a sulfonamide micromolecule inhibitor with purine and pyrrolopyrimidine parent nucleus.
Background
At present, the main treatment methods of malignant tumors are 3, which are surgical resection, radiotherapy and chemotherapy, but the 3 treatment methods have great limitations at the present stage. The tumor molecule targeted therapy takes specific molecules existing in malignant tumor tissues or cells as targets, adopts the drugs capable of specifically combining the target molecules to specifically kill the malignant tumor cells and does not kill the surrounding normal tissue cells, has the advantages of strong selectivity and high safety, and is one of the more conventional methods for treating malignant tumors at present.
The discovery of the first drug of the mTOR target has been in the history of nearly 60 years, but as a Changqing target, the development of mTOR is continuously broken through.
The marketed drugs are mainly rapamycin and analogues thereof, and the small molecule inhibitor taking mTOR as a target is currently clinically tested, so that the small molecule inhibitor taking mTOR as the target still has a larger research and development space.
Targeted drug therapy has made great progress in recent years. In the tumor microenvironment, the PI3K/Akt/mTOR signaling pathway is crucial. Clinical research results show that the inhibition of the PI3K/Akt/mTOR signaling pathway has reliable effect on a plurality of late malignant tumors. However, to date there is no very effective small molecule inhibitor targeting mTOR, suggesting that developing small molecule drugs that target mTOR therapy is a challenging process.
Disclosure of Invention
The invention aims to solve the existing problems and provides a sulfonamide small molecule inhibitor with a purine and pyrrolopyrimidine parent nucleus.
The invention is realized by the following technical scheme:
a sulfonamide micromolecule inhibitor with purine and pyrrolopyrimidine parent nucleus is synthesized by the following steps:
(1) Firstly weighing a compound 2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine (1g, 5.32mmol), dissolving the compound by using 20ml of methanol, placing the solution in an ice water bath, gradually dropping morpholine (0.87mL, 10.64mmol), heating the reaction system to normal temperature, stirring for half H, filtering, and taking a filter cake;
(2) Weighing compound a, dissolving in 10ml n-butanol, dripping 1.1ml morpholine, adding 0.93ml trifluoroacetic acid, heating to 125 deg.C, heating under reflux, stirring for 12 hr, and spottingDetecting the reaction, when the compound a is completely reacted, cooling the system to room temperature, and using saturated NaHCO 3 Solution and H 2 Washing the crude product, and separating and purifying the crude product by using column layer silica gel;
(3) Weighing compound b and p-benzyl bromobenzenesulfonyl chloride, dissolving in 10ml dichloromethane, and adding CsCO 3 Stirring at normal temperature for 6h, spotting a plate to monitor the reaction, filtering inorganic salt after the reaction of the p-benzyl bromobenzene sulfonyl chloride is finished, adding silica gel powder to prepare a sample, and separating and purifying the crude product by column chromatography;
(4) Weighing the compound c, dissolving the compound c in 5ml of anhydrous dichloromethane, and adding K 2 CO 3 Dropwise adding 0.28mmol of different fatty amine, stirring at normal temperature for reaction for 1h, performing dot-plate detection reaction, filtering inorganic salt after the compound c is reacted, adding silica gel powder for sample preparation, and separating and purifying the crude product by column chromatography;
(5) Weighing a compound 2, 6-dichloropurine, dissolving the compound with 20ml of methanol, placing the solution in an ice water bath, gradually dripping morpholine, heating a reaction system to normal temperature, stirring for half an hour, filtering, and taking a filter cake;
(6) Weighing compound d, dissolving in 10ml n-butanol, dripping 1.1ml morpholine, adding 0.93ml trifluoroacetic acid, heating to 125 deg.C, heating, refluxing, stirring for 12 hr, detecting by spot plate, and cooling to room temperature after compound d reacts completelyWith saturated NaHCO 3 Solution and H 2 Washing the crude product by using column layer silica gel to separate and purify the crude product;
(7) Weighing compound e and p-benzyl bromobenzenesulfonyl chloride, dissolving in 10ml dichloromethane, adding CsCO 3 Stirring at normal temperature for 6h, spotting a plate to monitor the reaction, filtering inorganic salt after the reaction of the p-benzyl bromobenzene sulfonyl chloride is finished, adding silica gel powder to prepare a sample, and separating and purifying the crude product by column chromatography;
(8) Weighing compound f, dissolving in 5ml of anhydrous dichloromethane, adding K 2 CO 3 And then dropwise adding 0.28mmol of different aliphatic amine, stirring at normal temperature for reaction for 1h, performing dot-plate detection reaction, filtering inorganic salt after the compound f finishes the reaction, adding silica gel powder for sample preparation, and separating and purifying the crude product by column chromatography.
Further, the 2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine in the step (1) is 1g,5.32mmol, and the morpholine is 0.87mL,10.64mmol.
Further, the compound a described in step (2) was 1g,4.19mmol, morpholine was 1.1g,12.57mmol, and trifluoroacetic acid was 1.43g,12.57mmol.
Further, the compound b described in the step (3) was 0.83g,2.87mmol, p-benzylbromobenzenesulfonyl chloride was 0.64g,2.39mmol, csCO 3 It was 1.38g and 7.17mmol.
Further, the compound c described in the step (4) was 0.1g,0.19mmol, K 2 CO 3 The yield was 0.13g,0.96mmol.
Further, the 2, 6-dichloropurine described in step (5) was 1g,5.32mmol.
Further, the compound d described in the step (6) was 1g,4.19mmol, morpholine was 1.1g,12.57mmol, and trifluoroacetic acid was 1.43g,12.57mmol.
Further, the compound e described in the step (7) was 0.83g,2.87mmol, p-benzylbromobenzenesulfonyl chloride was 0.64g,2.39mmol, csCO 3 It was 1.38g and 7.17mmol.
Further, the compound f described in the step (7) was 0.1g,0.19mmol, K 2 CO 3 The content was 0.13g,0.96mmol.
Compared with the prior art, the invention has the following advantages:
1. the application selects 2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine and 2, 6-dichloropurine as mother nucleus, and introduces sulfonamide group as active group to carry out a series of compound designs. And 30 brand new compounds were synthesized. The activity of A549 cells is tested, and the activity of three compounds reaches below 10 mu M, so that the compounds are expected to be further researched and become small molecule inhibitors which effectively target mTOR targets.
2. Purine and pyrrolopyrimidine compounds are mother cores of common targeted small-molecule inhibitors, combined with existing targeted mTOR small-molecule inhibitor effective tablets purine and pyrrolopyrimidine compounds are mother cores of common targeted small-molecule inhibitors, combined with existing targeted mTOR small-molecule inhibitor effective fragments a and b, the targeted mTOR small-molecule inhibitors taking purine and pyrrolopyrimidine as the mother cores are designed. The purine and the pyrrolopyrimidine are used as mother nuclei to be spliced with benzene sulfonamide groups respectively, so that the product is obtained. After characterization of these compounds, biological tests are performed, and it is hoped that small molecule compounds with inhibitory effect on mTOR targets can be screened out.
3. The mother nucleus of the pyridine sulfonamide clinical medicine is replaced by purine and pyrrolopyrimidine, and a hydrophobic pore channel formed by hydrogen bond or other actions with mTOR is hopefully reserved; the R group is introduced to search the influence of different substituents on the activity of the compound, and is different small molecules containing amino groups, such as cyclic amine, linear amine, branched amine and the like, and the hydrophilicity of the compound is expected to be enhanced, and the interaction with mTOR is also enhanced through hydrogen bonds. These are based on the design strategy of existing small molecule inhibitors targeting the PI3K/Akt/mTOR signaling pathway. The benzene sulfonamide concept is to replace the sulfonamide group used by some clinical drugs with a benzene sulfonamide group by consulting a large number of related inhibitors of the PI3K/Akt/mTOR signaling pathway and related documents, and hopefully, the activity of the compound and the combination of mTOR can be enhanced.
Detailed Description
A sulfonamide micromolecule inhibitor with purine and pyrrolopyrimidine parent nucleus is synthesized by the following steps:
(1) Weighing a compound 2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine, dissolving the compound with 20ml of methanol, placing the solution in an ice-water bath, gradually dripping morpholine, heating a reaction system to normal temperature, stirring for half an hour, and filtering to obtain a filter cake;
(2) Weighing compound a (1g, 4.19mmol), dissolving in 10ml n-butanol, dripping 1.1ml morpholine (1.1g, 12.57mmol), adding 0.93ml trifluoroacetic acid (1.43g, 12.57mmol), heating the system to 125 deg.C, heating under reflux, stirring for 12 hr, detecting reaction by dot plate, cooling the system to room temperature after compound a completely reacts, and adding saturated NaHCO 3 Solution and H 2 Washing the crude product, and separating and purifying the crude product by using column layer silica gel;
(3) Compound b (0.83g, 2.87mmol) and p-benzylbromobenzenesulfonyl chloride (0.64g, 2.39mmol) are first weighed and dissolved in 10ml of dichloromethane, and CsCO is then added 3 (1.38g, 7.17mmol), stirring at room temperature for 6h, and spottingMeasuring the reaction, filtering inorganic salt after the reaction of the p-benzyl bromide benzenesulfonyl chloride is finished, adding silica gel powder for sample preparation, and separating and purifying the crude product by column chromatography;
(4) Compound c (0.1g, 0.19mmol) is first weighed and dissolved in 5ml of anhydrous dichloromethane, and K is added 2 CO 3 (0.13g, 0.96mmol), dropwise adding different fatty amines, stirring at normal temperature for reaction for 1h, detecting by a dot plate, filtering inorganic salt after the compound c reacts, adding silica gel powder for sample preparation, and separating and purifying the crude product by column chromatography;
(5) Weighing compound 2, 6-dichloropurine (1g, 5.32mmol), dissolving with 20ml methanol, placing in ice water bath, gradually dropping morpholine, heating reaction system to normal temperature, stirring for half an hour, filtering, and collecting filter cake;
(6) Weighing compound d (1g, 4.19mmol), dissolving in 10ml n-butanol, dripping 1.1ml morpholine (1.1g, 12.57mmol), adding 0.93ml trifluoroacetic acid (1.43g, 12.57mmol), heating the system to 125 deg.C, heating under reflux, stirring for 12 hr, detecting reaction by dot plate, cooling the system to room temperature after compound d completely reacts, and adding saturated NaHCO 3 Solution and H 2 Washing the crude product by using column layer silica gel to separate and purify the crude product;
(7) Compound e (0.83g, 2.87mmol) and p-benzylbromobenzenesulfonyl chloride (0.64g, 2.39mmol) were first weighed out and dissolved in10ml of dichloromethane, then addition of CsCO 3 (1.38g, 7.17mmol), stirring at normal temperature for 6h, monitoring the reaction by a point plate, filtering inorganic salt after the reaction of the p-benzyl bromobenzene sulfonyl chloride is finished, adding silica gel powder for sample preparation, and separating and purifying the crude product by column chromatography;
(8) Compound f (0.1g, 0.19mmol) is first weighed and dissolved in 5ml of anhydrous dichloromethane, and K is added 2 CO 3 (0.13g and 0.96mmol), dropwise adding different aliphatic amine 0.28mmol, stirring at normal temperature for reaction for 1h, detecting the reaction by a dot plate, filtering inorganic salt after the compound f finishes the reaction, adding silica gel powder for sample preparation, and separating and purifying the crude product by column chromatography.
The structural formulae and nomenclature of the 30 compounds synthesized are shown in table 1 below:
table 1 structural formulas and names of 30 synthesized compounds
The MTT experiment was performed on the synthesized compounds, and the results are shown in table 2 below:
TABLE 2 IC of A549 inhibiting compounds 50
| Compound (I) | IC 50 (μM) |
| ZLN-11 | 2.048 |
| ZLN-23 | 4.925 |
| ZLN-26 | 4.405 |
| ZLN-28 | NA |
| ZLN-29 | 37.16 |
| ZLN-30 | NA |
Note: NA indicates no activity or poor linearity, and the corresponding IC cannot be calculated 50 The value is obtained.
MTT experiments show that the tested compound has a certain inhibition effect on A549, the activity of the compound is relatively better than that of a small molecular compound with R group of N-ethylpiperazine, the activity of the compounds ZLN-11 and ZLN-26 is less than 10 mu M, and the activity of a pyrrolopyrimidine mother nucleus is better than that of a compound with a purine mother nucleus, which is probably that the pyrrolopyrimidine skeleton has one N more than the purine mother nucleus, so that the binding with a target is enhanced.
When the tail is a cyclic aliphatic amine, the activity is better than that of a chain aliphatic amine compound, wherein the activity of the aliphatic amine containing a branched chain is slightly better than that of a linear aliphatic amine, and the fact that different R groups have an influence on the activity of the whole compound is proved.
Claims (9)
1. A sulfonamide micromolecule inhibitor with purine and pyrrolopyrimidine parent nucleus is characterized by comprising the following synthesis steps:
(1) Weighing a compound 2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine, dissolving the compound with 20ml of methanol, placing the solution in an ice-water bath, gradually dripping morpholine, heating a reaction system to normal temperature, stirring for half an hour, and filtering to obtain a filter cake;
(2) Weighing compound a, dissolving in 10ml n-butanol, dripping 1.1ml morpholine, adding 0.93ml trifluoroacetic acid, heating the system to 125 deg.C, heating, refluxing, stirring for 12 hr, detecting reaction by dot plate, cooling to room temperature after compound a completely reacts, and adding saturated NaHCO 3 Solution and H 2 Washing the crude product, and separating and purifying the crude product by using column layer silica gel;
(3) Weighing the compound b and the p-benzylbromobenzenesulfonyl chloride, dissolving the compound b and the p-benzylbromobenzenesulfonyl chloride in 10ml of dichloromethane, and adding CsCO 3 Stirring at normal temperature for 6h, spotting a plate to monitor the reaction, filtering inorganic salt after the reaction of the p-benzyl bromobenzene sulfonyl chloride is finished, adding silica gel powder to prepare a sample, and separating and purifying the crude product by column chromatography;
(4) Weighing compound c, dissolving in 5ml of anhydrous dichloromethane, adding K 2 CO 3 Dropwise adding 0.28mmol of different fatty amine, stirring at normal temperature for reaction for 1h, performing dot-plate detection reaction, filtering inorganic salt after the compound c is reacted, adding silica gel powder for sample preparation, and separating and purifying the crude product by column chromatography;
(5) Weighing a compound 2, 6-dichloropurine, dissolving the compound with 20ml of methanol, placing the solution in an ice water bath, gradually dripping morpholine, heating a reaction system to normal temperature, stirring for half an hour, filtering, and taking a filter cake;
(6) Weighing compound d, dissolving in 10ml n-butanol, dripping 1.1ml morpholine, adding 0.93ml trifluoroacetic acid, heating to 125 deg.C, heating under reflux and stirring for 12 hr, detecting reaction by dot plate, cooling to room temperature after compound d reacts completely, and adding saturated NaHCO 3 Solution and H 2 Washing the crude product by using column layer silica gel to separate and purify the crude product;
(7) Weighing compound e and p-benzyl bromobenzenesulfonyl chloride, dissolving in 10ml dichloromethane, adding CsCO 3 Stirring at normal temperature for 6h, performing spot plate monitoring reaction, filtering inorganic salt after the reaction of the p-benzylbromobenzenesulfonyl chloride is finished, adding silica gel powder for sample preparation, and separating and purifying a crude product by using column chromatography;
(8) Weighing compound f, dissolving in 5ml of anhydrous dichloromethane, adding K 2 CO 3 And then dropwise adding different 0.28mmol of aliphatic amine, stirring at normal temperature for reaction for 1 hour, carrying out dot plate detection reaction, filtering inorganic salt after the compound f finishes the reaction, adding silica gel powder for sample preparation, and separating and purifying the crude product by column chromatography.
2. The sulfonamide small molecule inhibitor with a purine and pyrrolopyrimidine parent nucleus, as claimed in claim 1, wherein the 2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine in step (1) is 1g,5.32mmol, and morpholine is 0.87mL,10.64mmol.
3. The sulfonamide small molecule inhibitor with purine and pyrrolopyrimidine nucleus according to claim 1, wherein compound a in step (2) is 1g,4.19mmol, morpholine is 1.1g,12.57mmol, and trifluoroacetic acid is 1.43g,12.57mmol.
4. The small molecule inhibitor of sulfonamide with purine and pyrrolopyrimidine nucleus according to claim 1, wherein the compound b in step (3) is 0.83g,2.87mmol, the p-benzylbromobenzenesulfonyl chloride is 0.64g,2.39mmol, csCO 3 It was 1.38g,7.17mmol.
5. The sulfonamide small molecule inhibitor with purine and pyrrolopyrimidine parent nucleus according to claim 1, wherein the compound c in step (4) is 0.1g,0.19mmol, K 2 CO 3 The content was 0.13g,0.96mmol.
6. The sulfonamide small molecule inhibitor with a purine and pyrrolopyrimidine parent nucleus according to claim 1, wherein the 2, 6-dichloropurine in step (5) is 1g,5.32mmol.
7. The sulfonamide small molecule inhibitor containing purine and pyrrolopyrimidine nucleus according to claim 1, wherein compound d in step (6) is 1g,4.19mmol, morpholine is 1.1g,12.57mmol, and trifluoroacetic acid is 1.43g,12.57mmol.
8. The small molecule inhibitor of sulfonamide with purine and pyrrolopyrimidine nucleus according to claim 1, wherein the compound e in step (7) is 0.83g,2.87mmol, the p-benzylbromobenzenesulfonyl chloride is 0.64g,2.39mmol, csCO 3 It was 1.38g and 7.17mmol.
9. The sulfonamide small molecule inhibitor with purine and pyrrolopyrimidine parent nucleus according to claim 1, wherein the compound f in step (7) is 0.1g,0.19mmol, K 2 CO 3 The yield was 0.13g,0.96mmol.
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