CN105732597B - A kind of midbody compound and the preparation method and application thereof preparing pyrrole amides class compound - Google Patents
A kind of midbody compound and the preparation method and application thereof preparing pyrrole amides class compound Download PDFInfo
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- CN105732597B CN105732597B CN201511018832.7A CN201511018832A CN105732597B CN 105732597 B CN105732597 B CN 105732597B CN 201511018832 A CN201511018832 A CN 201511018832A CN 105732597 B CN105732597 B CN 105732597B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 343
- -1 pyrrole amides Chemical class 0.000 title claims abstract description 279
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims description 51
- 238000000034 method Methods 0.000 claims abstract description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 55
- 239000001257 hydrogen Substances 0.000 claims abstract description 55
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 51
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 51
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 43
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 36
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 33
- 150000002367 halogens Chemical class 0.000 claims abstract description 33
- 230000008569 process Effects 0.000 claims abstract description 25
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 23
- 150000002431 hydrogen Chemical group 0.000 claims abstract 29
- 239000002904 solvent Substances 0.000 claims description 144
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 101
- 229910052757 nitrogen Inorganic materials 0.000 claims description 87
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 82
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 76
- 239000012043 crude product Substances 0.000 claims description 70
- 238000003756 stirring Methods 0.000 claims description 60
- 239000007787 solid Substances 0.000 claims description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 42
- 150000008282 halocarbons Chemical class 0.000 claims description 42
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 239000012074 organic phase Substances 0.000 claims description 28
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 26
- 239000012046 mixed solvent Substances 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 21
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 21
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 21
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 21
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 21
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 21
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 20
- 238000004440 column chromatography Methods 0.000 claims description 19
- 238000002953 preparative HPLC Methods 0.000 claims description 19
- HBXVLQNYPMSTEN-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]-2,5-dihydropyrrole-3-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1CC(=CC1)C(=O)O HBXVLQNYPMSTEN-UHFFFAOYSA-N 0.000 claims description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 18
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 14
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 14
- NAAPACORKFWKSI-UHFFFAOYSA-N COC(C(OC(=O)N(OCCCCC)OC(C)(C)C)(OCCC)OCC)CCCC(OCC(C)C)(OCCCC)OC(C)C Chemical compound COC(C(OC(=O)N(OCCCCC)OC(C)(C)C)(OCCC)OCC)CCCC(OCC(C)C)(OCCCC)OC(C)C NAAPACORKFWKSI-UHFFFAOYSA-N 0.000 claims description 13
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 10
- 238000007865 diluting Methods 0.000 claims description 10
- 238000010790 dilution Methods 0.000 claims description 10
- 239000012895 dilution Substances 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- NLXXVSKHVGDQAT-UHFFFAOYSA-N o-(oxan-2-yl)hydroxylamine Chemical compound NOC1CCCCO1 NLXXVSKHVGDQAT-UHFFFAOYSA-N 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 7
- 125000005518 carboxamido group Chemical group 0.000 claims description 7
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 claims description 7
- 229960001701 chloroform Drugs 0.000 claims description 7
- 229960003750 ethyl chloride Drugs 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- CPPKAGUPTKIMNP-UHFFFAOYSA-N cyanogen fluoride Chemical compound FC#N CPPKAGUPTKIMNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 230000001376 precipitating effect Effects 0.000 claims description 5
- 239000007821 HATU Substances 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- LQVMZVKOVPITOO-UHFFFAOYSA-N 9h-fluoren-1-ylmethyl carbonochloridate Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)Cl)=CC=C2 LQVMZVKOVPITOO-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- JTPUMZTWMWIVPA-UHFFFAOYSA-O Isopropamide Chemical compound C=1C=CC=CC=1C(C(N)=O)(CC[N+](C)(C(C)C)C(C)C)C1=CC=CC=C1 JTPUMZTWMWIVPA-UHFFFAOYSA-O 0.000 claims 2
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- JEVCWSUVFOYBFI-UHFFFAOYSA-N cyanyl Chemical compound N#[C] JEVCWSUVFOYBFI-UHFFFAOYSA-N 0.000 claims 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention discloses a kind of midbody compounds for preparing pyrrole amides class compound, as shown in formula I: where R1、R2、R3、R4Separately or concurrently it is selected from hydrogen, hydroxyl, cyano, halogen, carboxyl, sulfonyl, C1~C6Alkyl, C1~C6Alkoxy, C1~C6Aminoalkyl, C2~C6Amide groups, C2~C6Aminoacyl, C3~C6Heterocycle, C3~C6Heterocycloalkenyl, phenoxy group, phenyl or substituted phenyl.The process route for preparing pyrrole amides class compound using type I compound of the present invention is short, and easy to operate, high production efficiency, low energy consumption, safe and environment-friendly, obtains with can be convenient and coughs up amides compound with good deacetylation enzyme inhibition activity.
Description
Technical Field
The invention relates to an intermediate compound for preparing pyrrole amide compounds, and a preparation method and application thereof.
Background
Inactivation of genes that control cell growth in the body is one of the hallmarks of tumorigenesis. Epigenetic mechanisms that cause gene inactivation mainly include DNA methylation, histone acetylation, and modifications of other components in chromatin higher order structures, which alter chromatin conformation, resulting in changes in gene transcription regulation, and dysregulation of gene transcription causing cell proliferation disorders, resulting in tumor production.
Over 40 years ago, Allfrey et al recognized that histone acetylation process is closely related to eukaryotic gene transcription regulation (Allfrey VG, Faulkner R, Mirsky AE.Acetolation and methylation of histones and in the regulation of RNA synthesis [ J].ProcNatl Acad Sci USA, 1964, 51: 786-794). Histone acetylation plays a central role in transcriptional regulation in eukaryotic cells. Acetylation of histones occurs at the epsilon-amino group of the N-terminally evolutionarily conserved lysine residue, with modifications at H3 and H4 more prevalent than H2A and H2B, and the more important acetylation site being Lys at H39And Lys14And Lys at H45，Lys8，Lys12And Lys16. Acetylation of HAT acetylates the amino group of N-terminal lysine in histone, eliminates the positive charge in the amino group, makes the negative charge of DNA molecule favorable to the development of DNA conformation, relaxes the structure of nucleosome, facilitates the contact of transcription factor and cooperative transcription activator with DNA molecule, and makes histone acetylation activate the transcription expression of specific gene. In contrast, deacetylation of histones is detrimental to the expression of specific genes (e.g.Rb, p21, p 27). Acetylation and deacetylation of histones into a switch for specific gene expression (Thiaglinggam S, Cheng KH, Lee HJ, ethyl. histonedeacetylases: unique planes in mapping the oligomeric histone code [ J].Ann N Y Acad Sci，2003，983：84-100)。
Histone acetylation is regulated by a pair of functionally antagonistic proteases Histone Acetyltransferases (HATs) and Histone Deacetylases (HDACs). In normal cells, the pair of enzymes is in a state of dynamic equilibrium. In general, increased histone acetylation levels are associated with increased gene transcription activity, while too low acetylation levels are associated with suppressed gene expression (Forsberg EC, Bresenick EH. Histone catalysis genes and promoters: long-ranging catalysis patterns in the chromatography world [ J ]. Bioessays, 2001, 23 (9): 820-. Studies have found that HDACs are overexpressed and recruited by transcription factors, leading to abnormal suppression of specific genes, leading to tumors and other diseases; inhibition of HDAC activity results in the growth arrest and apoptosis of many cancer cells (Somech R, Izraeli S, J Simon A. Histone deacetylase inhibitors-a new tool to treat cancer [ J ]. cancer treat Rev, 2004, 30 (5): 461-. Therefore, HDACs have become the newest and most popular target in the current field of antineoplastic drug development.
HDAC inhibitors, which inhibit HDAC enzymatic activity, act by inhibiting HDAC, blocking the inhibition of gene expression due to dysfunction of HDAC recruitment, and modifying chromatin structure by altering histone acetylation, thereby modulating gene expression to treat cancer. It has obvious curative effect on treating blood system tumor and solid tumor by inducing growth arrest, differentiation or apoptosis of tumor cell. HDAC inhibitors are tumor specific and cytotoxic to proliferating and quiescent variant cells, whereas normal cells are more than 10-fold tolerant to them and do not cause growth arrest and apoptosis in normal cells. Moreover, the clinical dosage of the HDAC inhibitor is far lower than the maximum tolerance of human bodies, and the toxicity to the organisms is lower. The development and utilization of HDAC inhibitors have become a new hotspot in tumor therapy.
Currently, HDAC inhibitors that have been investigated and developed can be divided into five major classes: (1) hydroxamic acid compounds, the functional group being hydroxamic acid, and representative examples thereof include TSA, SAHA (Curtin ML, Garland RB, Heyman HR, et a1. succinimidyl hydroxamic acids as pore inhibitors of hormone deacylase [ J ]. Bioorg Medchem, 2002, 12 (20): 2919-; (2) cyclic tetrapeptides containing 2-amino-8-oxo-9, 10-epoxydecanoyl group or not containing the group, such as FK-228; (3) benzamide compound, representative MS-275, has entered clinical studies; (4) short chain fatty acids such as butyric acid and phenylbutyric acid; (5) other classes of HDAC inhibitors do not have the structural features of common HDACs, but all contain some or all of the structural subunits required for inhibiting HDAC activity.
For example, chinese patent CN 103420917 a discloses a benzamide compound containing a fused ring structure, as shown in formula a, which has histone deacetylase inhibitory activity and application in treating malignant tumor and differentiation and proliferation related diseases; chinese patent CN 103288728A discloses a naphthamide derivative, shown as formula B, which can effectively treat partial diseases caused by abnormal regulation of protein kinase; chinese patent CN 103539695A discloses a substituted diphenyl ether histone deacetylase inhibitor, which is shown in formula C; chinese patent CN 103467359A discloses a cinnamamide histone deacetylase inhibitor containing indole, which is shown in formula D; chinese patent CN 102659630 a discloses hydroxamic acid compounds, as shown in formula E.
Chinese patent CN 102786458A discloses a pyrrole carboxamide derivative, represented by formula F, which is used as an anti-malignant tumor drug, in particular, in the preparation of drugs for treating breast cancer, lung cancer and gastric cancer.
R1，R2，R3，R4Comprises the following steps: C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl;
R5，R6simultaneously or separately: hydrogen, C1-C6 alkyl; hydroxyl, halogen, C1-C4 alkoxy, and nitrate substituted C1-C6 alkyl.
At present, SAHA developed by Merck is a histone deacetylase inhibitor which is already on the market, is only limited to the treatment of T cell lymphoma of skin, and has no obvious curative effect on other cancers. Other developed HDAC inhibitors also have certain problems in the aspects of anticancer activity, toxic and side effects, subtype selectivity, and the like. Therefore, the development of a novel compound having histone deacetylase inhibitory activity is of great social and economic significance.
No report has been made on the use of the novel compounds of formula I for the preparation of histone deacetylase inhibitors.
Disclosure of Invention
The invention aims to provide an intermediate compound for preparing a pyrrole amide compound.
The invention provides an intermediate compound for preparing a pyrrole amide compound, which is shown as a formula I:
wherein R is1、R2、R3、R4Independently or simultaneously selected from hydrogen, hydroxy, cyano, halogen, carboxy, sulfonyl, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl, phenoxy, phenyl or substituted phenyl of (a).
Further, the intermediate compound is shown as a formula II, a formula III, a formula VI or a formula V:
wherein,
R5selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl or phenoxy group of (a);
R6selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl, phenoxy, phenyl or substituted phenyl of (a);
x is selected fromA group, m ═ 0, 1,2 or 3, n ═ 0, 1 or 2;
R7selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C1～C6Aminoalkyl of (C)2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R8、R9independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a).
Further, in the above-mentioned case,
R1、R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isopropylamino, n-butylamido, isobutylamino, tert-butylamino, pentylamino, hexylamino, Czocyclo-butyrylamino, pentanoylamino, hexanoylamino, carbamyl, alanyl, butyryl, pentanoyl, hexanoyl3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl or substituted phenyl;
R5selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, acetylamino, n-propionamido, isopropanamido, n-butylamido, isobutanoylamino, tert-butyrylamino, pentanamido, hexanamido, methionyl, ethanamido, n-alaninyl, iso-alaninyl, n-butylamido, iso-butylamido, tert-butylamido, pentylamino, hexylamino, Cn-butylamido, N-butylamido, tert-butylamido, pentylamino, hexylamino3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl or phenoxy;
R6selected from hydrogen, hydroxy, cyano, fluoro, chloroBromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, acetylamino, n-propionamido, isopropanamido, n-butylamido, isobutylamide, tert-butylamido, pentanamide, hexanamide, methionyl, ethanamide, n-alaninyl, isoalaninyl, n-butylamido, isobutylamino, tert-butylamido, pentylamino, hexylamino, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl or substituted phenyl;
m is 1 or 2, n is 1 or 2;
R7selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropylamido, n-butylamido, isobutylamino, tert-butyrylamino, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isoalanyl, n-butylamido, isobutylamino, tert-butylamido, pentylamino, hexylamino, Czocyclo, butylamino, pentanoylamino, hexanoylamino, N-butylamido, tert3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, (methylamino) methyl, (methylamino) ethyl, (methylamino)Propyl, (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (ethylamino) methyl, (ethylamino) ethyl, (ethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (propylamino) methyl, (propylamino) ethyl, (propylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentaalkylpiperazinyl, or hexanalkylpiperazinyl;
R8、R9independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isopropylamino, n-butylamido, isobutylamino, tert-butylamino, pentylamino, hexylamino, Czocyclo-butyrylamino, pentanoylamino, hexanoylamino, carbamyl, alanyl, butyryl, pentanoyl, hexanoyl3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl.
Further, the intermediate compound shown in the formula I is:
the invention also provides a preparation method of the intermediate compound shown in the formula I, and the synthetic route is as follows:
(1)
(2)
wherein, Boc represents tert-butyloxycarbonyl; TFA represents trifluoroacetic acid; Fmoc-Cl represents fluorenylmethoxycarbonyl chloride; HATU stands for 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; DIEA represents N, N-diisopropylethylamine;
a. stirring a mixed solvent of a compound IM-4, lithium hydroxide and an ether solvent/water at the temperature of 20-30 ℃ for reaction for 1-6 h, removing the organic solvent, adding water for dilution, adjusting the pH value to 3-6, precipitating a solid, and filtering to obtain a solid; washing and drying the solid to obtain N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid;
the molar ratio of the compound IM-4 to the lithium hydroxide is 1: 1-10; the mass-volume ratio of the compound IM-4 to the mixed solvent is 1: 7-20 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
b. at the temperature of 0-5 ℃, dissolving the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid obtained in the step a in a halohydrocarbon solvent, adding trifluoroacetic acid, and stirring and reacting at the temperature of 20-30 ℃ for 2-12H to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-3;
the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the halohydrocarbon solvent is 1: 5-20 g/ml; the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the trifluoroacetic acid is 1: 2-10 g/ml;
c. b, stirring the compound IM-3 obtained in the step b, sodium carbonate, fluorenyloxycarbonyl chloride and a mixed solvent of an ether solvent and water at the temperature of 20-30 ℃ for reaction for 12-16 h, adding water for dilution, adjusting the pH value to 1-3, extracting by using the ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a compound IM-2;
the molar ratio of the compound IM-3, sodium carbonate and fluorenyloxycarbonyl chloride is 1: 1-5: 0.9 to 1.5; the mass-volume ratio of the compound IM-3 to the mixed solvent is 1: 10-25 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
d. c, stirring and reacting the compound IM-2, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at the temperature of 25-30 ℃ for 12-16H, adding water for diluting, extracting with an ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-1;
the molar ratio of the compound IM-2, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 1-2: 1-2: 2-4; the mass-volume ratio of the compound IM-2 to the halocarbon solvent is 1: 9-20 g/ml;
e. d, stirring the compound IM-1, piperidine and the nitrogen-containing solvent in the step d at 25-30 ℃ for reaction for 4-6 h, adding water for dilution, extracting by using an ester solvent, combining organic phases, and drying, filtering and concentrating the organic phases to obtain a compound IM;
the mass-to-volume ratio of the compound IM-1 to piperidine is 1: 1-4 g/ml; the mass volume ratio of the compound IM-1 to the nitrogen-containing solvent is 1: 5-20 g/ml.
Further, the method comprises the following steps:
a. stirring a mixed solvent of a compound IM-4, lithium hydroxide and an ether solvent/water at 25 ℃ for 2 hours, removing the organic solvent, adding water for dilution, adjusting the pH to be 5, precipitating a solid, and filtering to obtain a solid; washing and drying the solid to obtain N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid;
the molar ratio of the compound IM-4 to the lithium hydroxide is 1: 4.5-5; the mass-volume ratio of the compound IM-4 to the mixed solvent is 1: 10-12 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 2: 1;
b. at the temperature of 0 ℃, dissolving the N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid obtained in the step a into a halohydrocarbon solvent, adding trifluoroacetic acid, and stirring and reacting at the temperature of 25 ℃ for 2 hours to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-3;
the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the halohydrocarbon solvent is 1: 10 g/ml; the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the trifluoroacetic acid is 1: 4-5 g/ml;
c. b, stirring the compound IM-3 obtained in the step b, sodium carbonate, fluorenyloxycarbonyl chloride and a mixed solvent of an ether solvent and water at 25 ℃ for 12-16 h, adding water for diluting, adjusting the pH value to 1, extracting by using an ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a compound IM-2;
the molar ratio of the compound IM-3, sodium carbonate and fluorenyloxycarbonyl chloride is 1: 3: 1; the mass-volume ratio of the compound IM-3 to the mixed solvent is 1: 20 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 5: 3;
d. c, stirring and reacting the compound IM-2, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at 25 ℃ for 12-16H, adding water for diluting, extracting with an ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-1;
the molar ratio of the compound IM-2, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 1.1: 1.2: 3; the mass-volume ratio of the compound IM-2 to the halocarbon solvent is 1: 9-10 g/ml;
e. d, stirring the compound IM-1, piperidine and the nitrogen-containing solvent in the step d at 25 ℃ for reacting for 4-6 h, adding water for diluting, extracting by using an ester solvent, combining organic phases, and drying, filtering and concentrating the organic phases to obtain a compound IM;
the mass-to-volume ratio of the compound IM-1 to piperidine is 1: 2 g/ml; the mass volume ratio of the compound IM-1 to the nitrogen-containing solvent is 1: 10 g/ml.
Further, in the steps a to e, the ether solvent is any one or more of tetrahydrofuran, diethyl ether, tert-butyl methyl ether, isopropyl ether and butyl ether; the halocarbon solvent is any one or more of dichloromethane, chloroethane, dichloroethane, trichloromethane and carbon tetrachloride; the ester solvent is one or more of ethyl acetate and ethyl formate; the nitrogen-containing solvent is one or more of N, N-dimethylformamide, N-dimethylacetamide, acetonitrile and pyridine.
The invention also provides another preparation method of the intermediate compound shown in the formula I, and the synthetic route is as follows:
or,
or
R5Selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl or phenoxy group of (a);
R6selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl, phenoxy, phenyl or substituted phenyl of (a);
x is selected fromA group, m ═ 0, 1,2 or 3, n ═ 0, 1 or 2;
R7selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C1～C6Aminoalkyl of (C)2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, phenylthio, and the like,Piperazinyl or substituted piperazinyl;
R8、R9independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R10selected from halogens;
the method comprises the following steps:
①, obtaining compound IM by the method;
②, compound IM of step ①, triethylamine,Reacting with halohydrocarbon solvent at 25-30 deg.c for 1-10 hr while stirring, and eliminating solvent to obtain coarse product; purifying the crude product by column chromatography to obtain a compound TM-1 (a); the compound IM, triethylamine,In a molar ratio of 1: 1-5: 1-2; the mass-volume ratio of the compound IM to the halocarbon solvent is 1: 50-100 g/ml;
or,
compound IM of step ①, triethylamine,Reacting with halohydrocarbon solvent at 25-30 deg.c for 1-10 hr while stirring, and eliminating solvent to obtain coarse product; purifying the crude product by column chromatography to obtain a compound TM-1 (b); the compound IM, triethylamine,In a molar ratio of 1: 1-5: 1-2; the mass-volume ratio of the compound IM to the halocarbon solvent is 1: 50-100 g/ml;
or,
compound IM of step ①, triethylamine,Reacting with halohydrocarbon solvent at 25-30 deg.c for 1-10 hr while stirring, and eliminating solvent to obtain coarse product; purifying the crude product by column chromatography to obtain a compound TM-1 (c); the compound IM, triethylamine,In a molar ratio of 1: 1-5: 1-2; the mass-volume ratio of the compound IM to the halocarbon solvent is 1: 50-100 g/ml.
Further, the method comprises the following steps
①, obtaining compound IM by the above method;
②, compound IM of step ①, triethylamine,Reacting with halohydrocarbon solvent at 25 deg.C under stirring for 2 hr, and removing solvent to obtain crude product; purifying the crude product by column chromatography to obtain a compound TM-1 (a); the compound IM, triethylamine,In a molar ratio of 1: 1.4: 1 to 1.2; the mass-volume ratio of the compound IM to the halocarbon solvent is 1: 80 g/ml;
or,
compound IM of step ①, triethylamine,Reacting with halocarbon solvent at 25 deg.C under stirring for 2 hr, removing solvent,obtaining a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 (b); the compound IM, triethylamine,In a molar ratio of 1: 1.4: 1 to 1.2; the mass-volume ratio of the compound IM to the halocarbon solvent is 1: 80 g/ml;
or,
compound IM of step ①, triethylamine,Reacting with halohydrocarbon solvent at 25 deg.C under stirring for 2 hr, and removing solvent to obtain crude product; purifying the crude product by column chromatography to obtain a compound TM-1 (c); the compound IM, triethylamine,In a molar ratio of 1: 1.4: 1 to 1.2; the mass-volume ratio of the compound IM to the halocarbon solvent is 1: 80 g/ml.
Further, in the above-mentioned case,
R5selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, acetylamino, n-propionamido, isopropanamido, n-butylamido, isobutanoylamino, tert-butyrylamino, pentanamido, hexanamido, methionyl, ethanamido, n-alaninyl, iso-alaninyl, n-butylamido, iso-butylamido, tert-butylamido, pentylamino, hexylamino, Cn-butylamido, N-butylamido, tert-butylamido, pentylamino, hexylamino3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl or phenoxy;
R6selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, acetylamino, n-propionamido, isopropanamido, n-butylamido, isobutanoylamino, tert-butyrylamino, pentanamido, hexanamido, methionyl, ethanamido, n-alaninyl, iso-alaninyl, n-butylamido, iso-butylamido, tert-butylamido, pentylamino, hexylamino, Cn-butylamido, N-butylamido, tert-butylamido, pentylamino, hexylamino3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl or substituted phenyl;
m is 1 or 2, n is 1 or 2;
R7selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropylamido, n-butylamido, isobutylamino, tert-butyrylamino, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isoalanyl, n-butylamido, isobutylamino, tert-butylamido, pentylamino, hexylamino, Czocyclo, butylamino, pentanoylamino, hexanoylamino, N-butylamido, tert3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenes ofA group, phenoxy group, phenyl group, substituted phenyl group, (methylamino) methyl group, (methylamino) ethyl group, (methylamino) propyl group, (dimethylamino) methyl group, (dimethylamino) ethyl group, (dimethylamino) propyl group, (ethylamino) methyl group, (ethylamino) ethyl group, (ethylamino) propyl group, (diethylamino) methyl group, (diethylamino) ethyl group, (diethylamino) propyl group, (propylamino) methyl group, (propylamino) ethyl group, (propylamino) propyl group, (dipropylamino) methyl group, (dipropylamino) ethyl group, (dipropylamino) propyl group, piperazinyl group, methylpiperazinyl group, ethylpiperazinyl group, propylpiperazinyl group, butanepiperazinyl group, pentaalkylpiperazinyl group, or hexanalkylpiperazinyl group;
R8、R9independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isopropylamino, n-butylamido, isobutylamino, tert-butylamino, pentylamino, hexylamino, Czocyclo-butyrylamino, pentanoylamino, hexanoylamino, carbamyl, alanyl, butyryl, pentanoyl, hexanoyl3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R10selected from fluorine, chlorine, bromine or iodine.
Further, theComprises the following steps:
further, in step ②, the halocarbon solvent is any one or more of dichloromethane, ethyl chloride, dichloroethane, chloroform, and carbon tetrachloride.
The invention also provides a method for preparing the pyrrole amide compound by using the intermediate compound shown in the formula I, and the synthetic route is as follows:
or,
or,
R5selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl or phenoxy group of (a);
R6selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl, phenoxy, phenyl or substituted phenyl of (a);
x is selected fromA group, m ═ 0, 1,2 or 3, n ═ 0, 1 or 2;
R7selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C1～C6Aminoalkyl of (C)2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R8、R9independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
the method comprises the following steps:
i. preparing an intermediate compound TM-1(a), TM-1(b) or TM-1(c) according to any one of the methods;
ii. Dissolving the compound TM-1(a) in the step i in a halohydrocarbon solvent at 0-5 ℃, adding trifluoroacetic acid, stirring and reacting at 25-30 ℃ for 1-12 h, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (a); the mass-volume ratio of the compound TM-1(a) to the halocarbon solvent is 1: 50-100 g/ml; the mass-to-volume ratio of the compound TM-1(a) to trifluoroacetic acid is 1: 10-50 g/ml;
or,
dissolving the compound TM-1(b) in the step i in a halohydrocarbon solvent at 0-5 ℃, adding trifluoroacetic acid, stirring and reacting at 25-30 ℃ for 1-12 h, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (b); the mass-volume ratio of the compound TM-1(b) to the halocarbon solvent is 1: 50-100 g/ml; the mass-to-volume ratio of the compound TM-1(b) to trifluoroacetic acid is 1: 10-50 g/ml;
or,
dissolving the compound TM-1(c) in the step i in a halohydrocarbon solvent at 0-5 ℃, adding trifluoroacetic acid, stirring and reacting at 25-30 ℃ for 1-12 h, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (c); the mass-volume ratio of the compound TM-1(c) to the halocarbon solvent is 1: 50-100 g/ml; the mass-to-volume ratio of the compound TM-1(c) to trifluoroacetic acid is 1: 10-50 g/ml.
Further, the method comprises the following steps:
i. preparing an intermediate compound TM-1(a), TM-1(b) or TM-1(c) according to the method;
ii. Dissolving the compound TM-1(a) in the step i in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, stirring at 25 ℃ for reacting for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (a); the mass-volume ratio of the compound TM-1(a) to the halocarbon solvent is 1: 60-65 g/ml; the mass-to-volume ratio of the compound TM-1(a) to trifluoroacetic acid is 1: 25 g/ml;
or,
dissolving the compound TM-1(b) in the step i in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, stirring at 25 ℃ for reacting for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (b); the mass-volume ratio of the compound TM-1(b) to the halocarbon solvent is 1: 60-65 g/ml; the mass-to-volume ratio of the compound TM-1(b) to trifluoroacetic acid is 1: 25 g/ml;
or,
dissolving the compound TM-1(c) in the step i in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, stirring at 25 ℃ for reacting for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (c); the mass-volume ratio of the compound TM-1(c) to the halocarbon solvent is 1: 60-65 g/ml; the mass-to-volume ratio of the compound TM-1(c) to trifluoroacetic acid is 1: 25 g/ml.
Further, in step ii, the halocarbon solvent is any one or more of dichloromethane, ethyl chloride, dichloroethane, chloroform and carbon tetrachloride.
The method for preparing the pyrrole amide compound by using the compound of the formula I has the advantages of short process route, simple and convenient operation, high production efficiency, low energy consumption, safety and environmental protection, and can conveniently obtain the pyrrole amide compound with good deacetylase inhibitory activity.
The following pyrrole amide compounds 1-26 with good deacetylase inhibitory activity are prepared from the compound shown in the formula I, and are shown in Table 1:
TABLE 1 Pyrrolinamide compounds prepared using the compounds of formula I of the present invention
Histone deacetylase plays an important role in the physiological and pathological processes of gene transcription regulation, signal transduction, growth and development, differentiation apoptosis, metabolic diseases, tumors and the like. If the activity of histone deacetylase is abnormal, a series of diseases with abnormal histone deacetylase activity can be caused. Including cell proliferative disorders, autoimmune disorders, inflammation, neurodegenerative disorders, viral disorders (for example, a review of the disorders in world patent WO2011011186 where HDAC6 inhibitors are useful).
The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum carbon atom content of a hydrocarbon group is indicated by a prefix, e.g., the prefix (C a-b) alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, (C1-4) alkyl refers to an alkyl group containing 1-4 carbon atoms.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by appropriately (e.g., equivalently) mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
In certain embodiments of the present invention, the invention includes isotopically-labeled compounds, which are intended to be identical to those recited herein, but wherein one or more atoms are replaced by another atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Can be incorporated in compounds of formula (I)Isotopes include hydrogen, carbon, nitrogen, oxygen, sulfur, i.e.2H,3H、13C、14C、15N、17O、18O、35And S. Compounds of formula (I) and stereoisomers thereof, and pharmaceutically acceptable salts of the compounds, stereoisomers, containing the aforementioned isotopes and/or other atomic isotopes are included within the scope of the invention.
The key intermediates and compounds in the present invention are isolated and purified by means of isolation and purification methods commonly used in organic chemistry and examples of such methods include filtration, extraction, drying, spin-drying and various types of chromatography. Alternatively, the intermediate may be subjected to the next reaction without purification.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
In the invention, Boc represents tert-butyloxycarbonyl; TFA represents trifluoroacetic acid; Fmoc-Cl represents fluorenyloxycarbonyl chloride; HATU stands for 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; DIEA represents N, N-diisopropylethylamine; DCM stands for dichloromethane.
Wherein, the raw materials: 4 '- ((dimethylamino) methyl)) - [1,1' -biphenyl ] -4-sulfonyl chloride can be obtained by purchasing a commercially available product, or can be obtained by the following production method:
1. preparation of 1- ([1,1' -biphenyl ] -4-yl) -N, N-dimethylmethylamine
Bromobenzene (1.5g,10mmol) was dissolved in 50mL of dioxane and 10mL of water, followed by addition of sodium carbonate (2.1g,20 mmol) and dimethyl butanediol 4- (N, N-dimethylaminomethyl) phenylboronate hydrochloride (2.6g,10mmol, manufacturer: Bailingwei science Co., Ltd.), and addition of [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (500 mg). The solution was replaced with nitrogen three times, and heated to 80 ℃ for 6 hours. After the reaction is finished, the organic solvent is removed from the reaction solution in vacuum, 200mL of water is added for dilution, dichloromethane is used for extraction for 3 times, organic phases are combined for drying, and the crude product is obtained through vacuum concentration. The crude product was subjected to column chromatography to give 1- ([1,1' -biphenyl ] -4-yl) -N, N-dimethylmethylamine as a white solid (1.1g, 52% yield).
MS(ESI)m/z212(M+1)+。
2. Preparation of 4 '- ((dimethylamino) methyl)) - [1,1' -biphenyl ] -4-sulfonyl chloride
1- ([1,1' -biphenyl ] -4-yl) -N, N-dimethylmethylamine (1.1g,5.2mmol) was dissolved in dichloromethane (20ml), and chlorosulfonic acid (5.0ml) was added dropwise under ice bath. The reaction solution was warmed to room temperature and kept at room temperature for stirring for 4 hours, then poured into ice water, and the solid was collected by filtration and dried under vacuum to give 4 '- ((dimethylamino) methyl)) - [1,1' -biphenyl ] -4-sulfonyl chloride (1.0g, 65% yield).
Example 1 preparation of Pyrrolic amides Using Compounds of formula I according to the invention
1. Preparation of 2, 5-dihydro-1H-pyrrole-3-carboxylic acid
Dissolving ethyl N-t-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylate (8.5g,36 mmol; manufacturer: Shaoshima technologies, Ltd.) in a mixed solution of 60mL tetrahydrofuran and 30mL water, adding lithium hydroxide (4.2g,176mmol), reacting at 25 ℃ with stirring for 2 hours, and removing the organic solvent in vacuo to obtain a residue; diluting the residue with an appropriate amount of water, adjusting the pH to 5 with 1N hydrochloric acid, precipitating a solid, and filtering to obtain a solid; the solid was washed with water and dried to give N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid (7.0g, 93% yield) as a white solid.
MS(ESI)m/z214(M+1)+。
Under an ice bath, dissolving N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid (7g,36mmol) in 70mL of dichloromethane solution, then dropwise adding 30mL of trifluoroacetic acid, stirring, slowly raising the temperature to 25 ℃, and continuing to stir for 2H to obtain a reaction solution; the reaction was concentrated to give 2, 5-dihydro-1H-pyrrole-3-carboxylic acid (4.0g, 99% yield) as a yellow oil.
MS(ESI)m/z114(M+1)+。
2. Preparation of N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid
2, 5-dihydro-1H-pyrrole-3-carboxylic acid (4.0g,35.4mmol) was dissolved in 50mL of tetrahydrofuran and 30mL of water, followed by addition of sodium carbonate (11.2g,106mmol) and fluorenyloxycarbonyl chloride (9.2g,35.4 mmol; manufacturer: Afahesa (China) chemical Co., Ltd.), and reaction with stirring at 25 ℃ overnight; after the reaction, 200mL of water was added to dilute the reaction mixture, the pH was adjusted to 1 with 2N hydrochloric acid, ethyl acetate was used for extraction, the organic phases were combined, dried and concentrated in vacuo to give N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid as a white solid (11.0g, 92% yield).
MS(ESI)m/z336(M+1)+。
3. Preparation of N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide
Dissolving N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid (11.0g, 32.8mmol) in 100mL of dichloromethane, sequentially adding O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (4.2g,36mmol), HATU (15g,39.4mmol) and DIEA (12.8g,98.4 mmol; manufacturer: Bailingwei Technology Co., Ltd.), and stirring at 25 ℃ for reacting overnight to obtain a reaction solution; adding 50mL of water into the reaction solution for dilution, extracting with ethyl acetate (50mL x 2), combining ethyl acetate phases, drying, filtering and concentrating the ethyl acetate phases to obtain a crude product; the crude product was purified by column chromatography to give N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide as a white solid (12g, 48% yield).
MS(ESI)m/z435(M+1)+。
4. Preparation of 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide
Dissolving N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -formamide (10g, 23mmol) in 100mL of DMF, adding 20mL of piperidine, stirring at 25 ℃ for reacting for 4 hours, then adding 800mL of water for diluting, extracting with ethyl acetate, and combining organic phases; the organic phase was dried, filtered and concentrated to give 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide as a white solid (4.5g, 92% yield).
MS(ESI)m/z213(M+1)+。
5. Preparation of 1- ((4-benzonitrile) sulfonyl) -N-hydroxy-2, 5-dihydro-1H-pyrrole-3-carboxamide
Dissolving 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -formamide (100mg,0.5mmol) and triethylamine (66mg,0.7mmol) in dichloromethane (8mL), adding 4-cyanobenzenesulfonyl chloride (125mg,0.5 mmol; manufacturer: Bailingwei Techno. Co., Ltd.) to the reaction solution at 25 ℃, stirring at 25 ℃ for 2 hours, and concentrating to remove the solvent to obtain a crude product; the crude product was purified by column chromatography to give 1- ((4-benzonitrile) sulfonyl) -N- ((tetrahydro-2H-pyran-2-yl) oxy) -2, 5-dihydro-1H-pyrrole-3-carboxamide (80mg, 39% yield) as a white solid.
MS(ESI)m/z 378(M+1)+。
Dissolving 1- ((4-benzonitrile) sulfonyl) -N- ((tetrahydro-2H-pyran-2-yl) oxy) -2, 5-dihydro-1H-pyrrole-3-formamide (80mg,0.3mmol) in 5mL of dichloromethane solution under ice bath, then dropwise adding 2mL of trifluoroacetic acid, stirring, slowly raising the temperature to 25 ℃, continuing stirring for reaction for 2H, and concentrating to remove the solvent to obtain a crude product; the crude product was purified by preparative high performance liquid chromatography to give 1- ((4-benzonitrile) sulfonyl) -N-hydroxy-2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid (13mg, 25% yield).
MS(ESI)m/z 294(M+1)+。
1HNMR(400MHz,DMSO-d6)δ10.80(br s,1H),8.13-8.11(m,2H),8.02-8.00(m,2H),6.32(s,1H),4.22-4.21(d,J＝2.4Hz,4H).
Example 2 preparation of Pyrrolic amides Using Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and benzenesulfonyl chloride (100mg,0.6 mmol; manufacturer: carbofuran technologies, Inc.) the intermediate compounds (shown below) and the final product (N-hydroxy-1- (benzenesulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid, 18mg, 14% yield) were prepared in a similar manner as in example 1.
Intermediate compounds:
MS(ESI)m/z 353(M+1)+。
the final product:
MS(ESI)m/z269(M+1)+。
1HNMR(400MHz,DMSO-d6)δ10.80(br s,1H),9.0(br s,1H),7.84-7.82(d,J＝7.6Hz,2H),7.74-7.70(m,1H),7.66-7.62(m,2H),6.30(s,1H),4.17(s,4H)。
example 3 preparation of Pyrrolic amides Using Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4-phenoxybenzenesulfonyl chloride (125mg,0.6 mmol; manufacturer: Bailingwei technologies, Ltd.), the intermediate compound (shown below) and the final product (N-hydroxy-1- ((4-phenoxyphenyl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid, 26mg, 16% yield) were prepared in a similar manner as in example 1.
Intermediate compounds:
MS(ESI)m/z 445(M+1)+。
the final product:
MS(ESI)m/z361(M+1)+。
1HNMR(400MHz,DMSO-d6)δ10.82(br s,1H),9.02(br s,1H),7.84-7.82(m,2H),7.50-7.46(m,2H),7.30-7.26(m,1H),7.18-7.12(m,4H),6.34(s,1H),4.16(s,4H)。
example 4 preparation of Pyrrolic amides Using Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4-acetamido-3-chlorobenzenesulfonyl chloride (150mg,0.6 mmol; manufacturer: Bailingwei science and technology Co., Ltd.), the intermediate compound (shown below) and the final product (white solid N-hydroxy-1- ((4-acetamido-3-chlorophenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide, 47mg, 10.7% yield) were prepared in a similar manner as in example 1.
Intermediate compounds:
MS(ESI)m/z 444(M+1)+。
the final product:
MS(ESI)m/z360(M+1)+。
1HNMR(400MHz,CD3OD)δ8.25-8.23(d,J＝8.8Hz,1H),7.74(d,J＝0.8Hz，1H),7.80-7.78(m,1H),6.38(s,1H),4.28(s,4H),2.25(s,3H)。
example 5 preparation of Pyrrolic amides Using Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-sulfonyl chloride (132mg,0.6 mmol; manufacturer: Bailingwei Techno Co., Ltd.), the intermediate compound (shown below) and the final product (white solid N-hydroxy-1- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin) -6-sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide, 12mg, 8.0% yield) were prepared in a similar manner as in example 1.
Intermediate compounds:
MS(ESI)m/z 411(M+1)+。
the final product:
MS(ESI)m/z327(M+1)+。
1HNMR(400MHz,DMSO-d6)δ10.80(s,1H),9.05(br s,1H),7.31-7.26(m,2H),7.09-7.07(d,J＝8.4Hz,1H),6.32(s,1H),4.34-4.31(m,4H),4.14(s,4H)。
example 6 preparation of Pyrrolic amides Using Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 2, 3-chroman-6-sulfonyl chloride (123mg,0.6 mmol; manufacturer: Bailingwei science and technology Co., Ltd.), the intermediate compounds (shown below) and the final product (white solid N-hydroxy-1- ((2, 3-chroman) -6-sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide, 10mg, 6.8% yield) were prepared in analogy to example 1.
Intermediate compounds:
MS(ESI)m/z 395(M+1)+。
the final product:
MS(ESI)m/z311(M+1)+。
1HNMR(400MHz,DMSO-d6)δ10.82(s,1H),9.05(br s,1H),7.69(d,J＝1.6Hz,1H),7.59-7.57(m,1H),6.96-6.94(d,J＝8.4Hz,1H),6.31(s,1H),4.67-4.62(t,J＝8.8Hz,2H),4.13(s,4H),3.29-3.24(t,J＝8.8Hz,2H)。
example 7 preparation of Pyrrolic amides Using Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4- (chlorosulfonyl) benzoic acid (124mg,0.6 mmol; manufacturer: Bailingwei science and technology Co., Ltd.), the intermediate compounds (shown below) and the final product (white solid N-hydroxy-1- ((4-formyloxy) -benzenesulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide, 116mg, 79% yield) were prepared in a similar manner as in example 1.
Intermediate compounds:
MS(ESI)m/z 397(M+1)+。
the final product:
MS(ESI)m/z 313(M+1)+。
1HNMR(400MHz,DMSO-d6)δ10.81(br s,1H),9.05(br s,1H),8.16-8.14(d,J＝8.4Hz,2H),7.96-7.94(d,J＝8.4Hz,3H),6.32(s,1H),4.40(s,4H)。
example 8 preparation of Pyrrolic amides Using Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4 '-methoxy- [1,1' -biphenyl ] -4-sulfonyl chloride (113mg,0.6 mmol; manufacturer: Bailingwei Techno Co., Ltd.), the intermediate compound (shown below) and the final product (N-hydroxy-1- (4 '-methoxy- [1,1' -biphenyl ] -4-sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid, 29mg, 7% yield) were prepared in a similar manner as in example 1.
Intermediate compounds:
MS(ESI)m/z 459(M+1)+。
the final product:
MS(ESI)m/z 375(M+1)+。
1HNMR(400MHz,DMSO-d6)δ10.81(br s,1H),9.05(br s,1H),7.90-7.85(m,4H),7.73-7.71(m,2H),7.08-7.06(m,2H),6.34(s,1H),4.20(s,4H),3.82(s,3H)。
example 9 preparation of Pyrrolic amides Using Compounds of formula I according to the invention
With 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxo) -carboxamide (100mg,0.5mmol) and 4- (tert-butyl) phenyl) sulfonyl chloride (130mg,0.6 mmol; the manufacturer: carbofuran technologies co., ltd.) as a starting material, intermediate compounds (shown below) and the final product (N-hydroxy-1- ((4- (tert-butyl) phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide, 10mg, 6% yield) were prepared according to the similar procedure in example 1.
Intermediate compounds:
MS(ESI)m/z 409(M+1)+。
the final product:
MS(ESI)m/z 325(M+1)+。
1HNMR(400Hz,CD3OD)δ7.81-7.79(m,2H),7.69-7.67(m,2H),6.36(s,1H),4.26(s,4H),1.37(s,9H)。
EXAMPLE 10 preparation of Pyrrolinamide Compounds from Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4- (methylaminocarbonyl) benzenesulfonyl chloride (128mg,0.6 mmol; manufacturer: Bailingwei science and technology Co., Ltd.), the intermediate compound (shown below) and the final product (white solid N-hydroxy-1- ((4- (methylaminocarbonyl) phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide, 25mg, 16% yield) were prepared in a similar manner as in example 1.
Intermediate compounds:
MS(ESI)m/z 410(M+1)+。
the final product:
MS(ESI)m/z 326(M+1)+。
1HNMR(400MHz,DMSO-d6)δ11.81(br s,1H),9.05(br s,1H),8.67(br s,1H),8.04-8.02(d,J＝8.4Hz,2H),7.93-7.91(d,J＝8.4Hz,3H),6.32(s,1H),4.20(s,4H)。
EXAMPLE 11 preparation of Pyrrolinamide Compounds from Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4- (acetamido) benzenesulfonyl chloride (128mg,0.6 mmol; manufacturer: Bailingwei science and technology Co., Ltd.), the intermediate compound (shown below) and the final product (white solid N-hydroxy-1- ((4-acetamidobenzene) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide, 15mg, 9.6% yield) were prepared in a similar manner as in example 1.
Intermediate compounds:
MS(ESI)m/z 410(M+1)+。
the final product:
MS(ESI)m/z 326(M+1)+。
1HNMR(400MHz,CD3OD)δ7.82(s,4H),6.38(s,1H),4.25(s,4H),2.17(s,3H)。
example 12 preparation of Pyrrolic amides Using Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxo) -carboxamide (100mg,0.5mmol) and 4-fluorobenzenesulfonyl chloride (109mg,0.6 mmol; manufacturer: carbofuran technologies, Inc.) the intermediate compounds (shown below) and the final product (N-hydroxy-1- ((4-fluorophenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid, 33mg, 25% yield) were prepared in analogy to example 1.
Intermediate compounds:
MS(ESI)m/z 371(M+1)+。
the final product:
MS(ESI)m/z 287(M+1)+。
1HNMR(400Hz,CD3OD)δ7.96-7.93(dd,J＝4.8，8.0Hz,2H),7.39-7.35(m,2H),6.4(s,1H),4.3(s,4H)。
example 13 preparation of Pyrrolic amides Using Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxo) -carboxamide (100mg,0.5mmol) and 3-fluorobenzenesulfonyl chloride (109mg,0.6 mmol; manufacturer: carbofuran technologies, Inc.) the intermediate compounds (shown below) and the final product (N-hydroxy-1- ((3-fluorophenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid, 33mg, 25% yield) were prepared in analogy to example 1.
Intermediate compounds:
MS(ESI)m/z 371(M+1)+。
the final product:
MS(ESI)m/z 287(M+1)+。
1HNMR(400Hz,CD3OD)δ＝8.17-8.12(m,J＝8.0Hz,2H),8.03-8.01(d,1H),7.89-7.85(m,1H),6.38(s,1H),4.31(s,4H)。
example 14 preparation of Pyrrolic amides Using Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4-methoxybenzenesulfonyl chloride (123mg,0.6 mmol; manufacturer: Bailingwei technologies Co., Ltd.), the intermediate compound (shown below) and the final product (N-hydroxy-1- ((4-methoxyphenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid, 34mg, 23% yield) were prepared according to a similar procedure as in example 1.
Intermediate compounds:
MS(ESI)m/z 383(M+1)+。
the final product:
MS(ESI)m/z 299(M+1)+。
1HNMR(400Hz,CD3OD)δ＝7.828-7.805(d,J＝8Hz,2H),7.145-7.123(d,J＝8.8Hz,2H),6.432(s,1H),4.242(s,4H),3.896(s,3H)。
EXAMPLE 15 preparation of Pyrrolinamide Compounds from Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 3-methoxybenzenesulfonyl chloride (123mg,0.6 mmol; manufacturer: Bailingwei technologies Co., Ltd.), the intermediate compound (shown below) and the final product (N-hydroxy-1- ((3-methoxyphenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid, 36mg, 24% yield) were prepared according to a similar procedure as in example 1.
Intermediate compounds:
MS(ESI)m/z 383(M+1)+。
the final product:
MS(ESI)m/z 299(M+1)+。
1HNMR(400Hz,DMSO-D6)δ＝10.80(s,1H),9.02(s,1H),7.59-7.55(m,1H),7.41-7.39(d,J＝8Hz,1H),7.30-7.27(m,2H),6.35(s,1H),4.19(s,4H),3.85(s,3H)。
EXAMPLE 16 preparation of Pyrrolinamide Compounds from Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4-methylbenzenesulfonyl chloride (114mg,0.6 mmol; manufacturer: Bailingwei technologies Co., Ltd.), the intermediate compound (shown below) and the final product (N-hydroxy-1- ((4-methylphenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid, 26mg, 19% yield) were prepared according to a similar procedure as in example 1.
Intermediate compounds:
MS(ESI)m/z 367(M+1)+。
the final product:
MS(ESI)m/z 283(M+1)+。
1HNMR(400MHz,CD3OD)δ＝7.76(d,J＝8.4Hz,2H),7.44(d,J＝8.0Hz,2H),6.35(s,1H),4.25(s,4H),2.45(s,3H)。
example 17 preparation of Pyrrolic amides Using Compounds of formula I in accordance with the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 3-methylbenzenesulfonyl chloride (114mg,0.6 mmol; manufacturer: Bailingwei technologies Co., Ltd.), the intermediate compound (shown below) and the final product (N-hydroxy-1- ((3-methylphenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid, 24mg, 18% yield) were prepared according to a similar procedure as in example 1.
Intermediate compounds:
MS(ESI)m/z 367(M+1)+。
the final product:
MS(ESI)m/z 283(M+1)+。
1HNMR(400MHz,CD3OD)δ＝7.70～7.66(m,2H),7.52～7.51(m,2H),6.36(s,1H),4.26(s,4H),2.46(s,3H)。
EXAMPLE 18 preparation of Pyrrolinamide Compounds Using Compounds of formula I in accordance with the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 3, 4-dimethoxybenzenesulfonyl chloride (114mg,0.6 mmol; manufacturer: Bailingwei science and technology Co., Ltd.), the intermediate compound (shown below) and the final product (white solid N-hydroxy-1- ((3, 4-dimethoxyphenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide, 24mg, 18% yield) were prepared in a similar manner as in example 1.
Intermediate compounds:
MS(ESI)m/z 413(M+1)+。
the final product:
MS(ESI)m/z 329(M+1)+。
1HNMR(400Hz,DMSO-D6)δ＝10.80(s,1H),9.13(s,1H),7.50-7.48(m,1H),7.31-7.24(m,2H),6.38(s,1H),4.24(s,4H),3.92(s,3H)。
EXAMPLE 19 preparation of Pyrrolinamide Compounds from Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4- (4-fluorophenyl) benzenesulfonyl chloride (162mg,0.6 mmol; manufacturer: Bailingwei science and technology Co., Ltd.), the intermediate compound (shown below) and the final product (white solid N-hydroxy-1- ((4- (4-fluorophenyl) phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide, 32mg, 18% yield) were prepared in analogy to example 1.
Intermediate compounds:
MS(ESI)m/z 447(M+1)+。
the final product:
MS(ESI)m/z 363(M+1)+。
1HNMR(400Hz,DMSO-D6)δ＝10.83(s,1H),9.02(s,1H),7.94-7.89(m,4H),7.84-7.80(m,2H),7.38-7.33(m,2H),6.35(s,1H),4.22(s,4H)。
EXAMPLE 20 preparation of Pyrrolinamide Compounds from Compounds of formula I according to the invention
With 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxo) -carboxamide (100mg,0.5mmol) and 4- (1,2, 36-tetrahydropyridin-4-yl) phenyl) sulfonyl chloride (114mg,0.6 mmol; the manufacturer: carbofuran technologies co., ltd.) as a starting material, intermediate compounds (shown below) and the final product (white solid N-hydroxy-1- ((4- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide, 26mg, 15% yield) were prepared according to the similar procedure in example 1.
Intermediate compounds:
MS(ESI)m/z 434(M+1)+。
the final product:
MS(ESI)m/z 350(M+1)+。
EXAMPLE 21 preparation of Pyrrolinamide Compounds from Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxo) -carboxamide (100mg,0.5mmol) and 4- (4-tert-butylphenyl) benzenesulfonyl chloride (184mg,0.6 mmol; manufacturer: Bailingwei science and technology Co., Ltd.), the intermediate compound (shown below) and the final product (white solid N-hydroxy-1- ((4- (4-tert-butylphenyl) phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide, 23mg, 12% yield) were prepared according to a similar procedure as in example 1.
Intermediate compounds:
MS(ESI)m/z 485(M+1)+。
the final product:
MS(ESI)m/z 401(M+1)+。
1HNMR(400Hz,DMSO-D6)δ＝10.83(s,1H),9.03(s,1H),7.92-7.87(m,4H),7.77(d,J＝8.4Hz,2H),7.53(d,J＝8.4Hz,2H),6.35(s,1H),4.22(s,4H)。
EXAMPLE 22 preparation of Pyrrolinamide Compounds from Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4- (4-morpholine-N-phenyl) benzenesulfonyl chloride (202mg,0.6 mmol; manufacturer: Bailingwei science and technology Co., Ltd.), the intermediate compound (shown below) and the final product (white solid N-hydroxy-1- ((4- (4-morpholine-N-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide, 45mg, 21% yield) were prepared in analogy to example 1.
Intermediate compounds:
MS(ESI)m/z 514(M+1)+。
the final product:
MS(ESI)m/z 430(M+1)+。
1HNMR(400Hz,DMSO-D6)δ＝10.83(s,1H),9.03(s,1H),7.87-7.82(m,4H),7.66(d,J＝8.4Hz,2H),7.05(d,J＝8.4Hz,2H),6.35(s,1H),4.18(s,4H),3.76-3.74(m,4H),3.51-3.50(m,4H)。
EXAMPLE 23 preparation of Pyrrolinamide Compounds from Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4- (4-dimethylaminomethyl-phenyl) benzenesulfonyl chloride (177mg,0.6 mmol; manufacturer: carbofuran technologies, inc.) in a similar manner as in example 1, the intermediate compound (shown below) and the final product (white solid N-hydroxy-1- ((4- (4-dimethylaminomethyl-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide, 36mg, 19% yield) were prepared.
Intermediate compounds:
MS(ESI)m/z 486(M+1)+。
the final product:
MS(ESI)m/z 402(M+1)+。
1HNMR(400Hz,DMSO-D6)δ＝10.85(s,1H),9.95(s,1H),9.03(s,1H),8.00-7.88(m,6H),7.63(d,J＝8.0Hz,2H),6.35(s,1H),4.35(s,2H),4.23(s,4H),2.77(s,6H)。
EXAMPLE 24 preparation of Pyrrolinamide Compounds from Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and (3-methyl-4-phenyl) benzenesulfonyl chloride (177mg,0.6 mmol; manufacturer: Bailingwei Techno Co., Ltd.), the intermediate compound (shown below) and the final product (preparation of N-hydroxy-1- (((3-methyl-4-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid, 33mg, 18% yield) were prepared in a similar manner as in example 1.
Intermediate compounds:
MS(ESI)m/z 443(M+1)+。
the final product:
MS(ESI)m/z 359(M+1)+。
1HNMR(400Hz,DMSO-D6)δ＝10.85(s,1H),9.04(s,1H),7.78(s,1H),7.72-7.70(m,1H),7.50-7.39(m,6H),6.37(s,1H),4.23(s,4H),2.33(s,3H)。
EXAMPLE 25 preparation of Pyrrolinamide Compounds from Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and (3-methyl-4-p-fluorophenyl) benzenesulfonyl chloride (177mg,0.6 mmol; manufacturer: Bailingwei Techno Co., Ltd.), the intermediate compound (shown below) and the final product (N-hydroxy-1- (((3-methyl-4-p-fluorophenyl) phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid, 29mg, 15% yield) were prepared in analogy to example 1.
Intermediate compounds:
MS(ESI)m/z 421(M+1)+。
the final product:
MS(ESI)m/z 377(M+1)+。
1HNMR(400Hz,DMSO-D6)δ＝10.85(s,1H),9.04(s,1H),7.78(s,1H),7.71-7.69(m,1H),7.48-7.45(m,3H),7.33-7.29(d,J＝8.0Hz,2H),6.37(s,1H),4.23(s,4H),2.32(s,3H)。
EXAMPLE 26 preparation of Pyrrolinamide Compounds from Compounds of formula I according to the invention
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4- (4-methylpiperazin-1-yl) phenylboronic acid pinacol ester (3.0g,10 mmol; manufacturer: Bailingwei science and technology Co., Ltd.), the intermediate compound (shown below) and the final product (N-hydroxy-1- ((4- (4-methylpiperazin-N-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide were prepared according to the preparation of 4 '- ((dimethylamino) methyl)) - [1,1' -biphenyl ] -4-sulfonyl chloride and the analogous procedure in example 1, 29mg, 15% yield).
Intermediate compounds:
MS(ESI)m/z 527(M+1)+。
the final product:
MS(ESI)m/z 443(M+1)+。
1HNMR(400Hz,DMSO-D6)δ＝10.84(s,1H),9.03(s,1H),7.91-7.84(m,4H),7.70(d,J＝8.4Hz,2H),7.13(d,J＝8.4Hz,2H),6.34(s,1H),4.20(s,4H),3.53(s,2H),3.27-3.08(m,6H),2.87(s,3H)。
the results of examples 1 to 26 show that the pyrrole amide compound prepared by using the compound of formula I has the advantages of short process route, simple operation, high production efficiency, low energy consumption, safety, environmental protection and capability of conveniently obtaining the pyrrole amide compound.
To illustrate the advantageous effects of the present invention, the present invention provides the following test examples:
test example 1 biological Activity assay
The HDA inhibitory activity of the compounds of the invention was tested in a substrate deacetylation assay.
A: detection of the enzyme activity of deacetylase 6 (#50076, BPS Bioscience):
the HDAC6 removes acetyl on the substrate, so that the substrate is activated, can be acted by a subsequently added color development solution and releases a fluorescent group, and the size of a fluorescent signal of the substrate reflects the activity of the HDAC 6. The IC50 detection method of the enzyme is disclosed in Chuping Xu, Elisabetta Soragni Improved Histone Deacetylase Inhibitors as therapeutics for the Neurgenic disease Friedreich's Ataxia: A New Synthetic Route. The total reaction (100. mu.L/well) contained 0.35 ng/. mu.L of HDAC6, 20. mu.M substrate and varying concentrations of compound. After incubation at 37 ℃ for 30 minutes, the fluorescence signal was measured, and the inhibition of the compound was determined from the data obtained and plotted against the compound concentration to obtain a concentration response curve, and the IC50 values were fitted according to a four parameter model.
B: deacetylase 3 enzyme activity assay (#50003, BPS Bioscience):
the HDAC3 removes acetyl on the substrate, so that the substrate is activated, can be acted by a color developing solution and releases a fluorescent group, and the size of a fluorescent signal of the substrate reflects the activity of the HDAC 3. The IC50 detection method of the enzyme is disclosed in Chuping Xu, Elisabettasoargi Improved Histone Deacetylase Inhibitors as Therapeutics for the Neuregenerative disease Friedreich's Ataxia: A New Synthetic Route. The total reaction (100. mu.L/well) contained 0.16 ng/. mu.L of HDAC3, 10. mu.M substrate and varying concentrations of compound. The fluorescence signal was detected on-line at Ex/Em ═ 360/460. The inhibition of the compound was determined from the data obtained and plotted against compound concentration to obtain a concentration response curve, and IC50 values were fitted according to a four parameter model.
The enzymatic activity of deacetylase 6 (i.e., HDAC6) was assayed according to the methods described above for pyrrole amide compounds 1-26 of examples 1-26, prepared using the compound of formula I of the present invention, and the results are shown in Table 2, wherein the IC50 of each compound was determined according to the indicated classification, and in Table 2:
"+" indicates that the IC50 assay for HDAC6 was greater than 500 nM;
"+ + +" indicates that IC50 for HDAC6 was less than 300nM and greater than 100 nM;
"+ + + + +" indicates that IC50 for HDAC6 was less than 100nM
The enzymatic activity of deacetylase 3 (i.e., HDAC3) was assayed according to the methods described above for pyrrole amide compounds 1-26 of examples 1-26, prepared using the compound of formula I of the present invention, and the results are shown in Table 2, wherein the IC50 of each compound was determined according to the indicated classification, and in Table 2:
"+" indicates that the IC50 assay for HDAC3 was greater than 1000 nM;
"+ + +" indicates that IC50 for HDAC3 was greater than 100nM and less than 1000 nM;
"+ + + + +" indicates that the IC50 for HDAC3 was less than 100 nM.
TABLE 2 inhibitory Activity of pyrrole amides 1-26 on HDAC6& HDAC3
Test results show that the pyrrole amide compounds 1-26 prepared from the compound of the formula I have good deacetylase inhibitory activity and have the potential of preventing and/or treating diseases caused by abnormal histone deacetylase activity.
Test example 2 cell assay-cell growth inhibition assay
Materials and reagents
HepG2 cell line, Hep3B cell line, HuH7 cell line and Li7 cell line were purchased from Shanghai Life sciences institute of Chinese academy of sciences; DMEM high-glucose medium and MEM medium were purchased from Hyclone; fetal bovine serum was purchased from Gibco; trypsin was purchased from Invitrogen Shanghai; the CCK-8 kit is purchased from Biyuntian Biotechnology institute (beyond time); the other consumables such as cell culture dishes were purchased from Corning China.
Cell preparation prior to Compound action
Digesting HepG2 cells, Hep3B cells, Huh7 cells and Li7 cells in logarithmic growth phase by trypsin, taking uniform cell suspension, counting, adjusting the cell density to 1500 cells/hole by using a culture medium containing 10% serum, re-inoculating the cells in a 96-hole cell culture plate, culturing the cells in a volume of 200 mu L at 37 ℃ and 5% CO2Culturing in an incubator; the culture was carried out for 24 hours and used for the experiment.
Action of the Compound
The cells cultured for 24 hours were taken out from the incubator, the culture solution in the well plate was aspirated, 200. mu.L of a compound solution prepared with a medium containing 10% fetal bovine serum was added to each well, each concentration was 5 in parallel, DMSO was set as a negative control, and the cells were cultured at 37 ℃ for 72 hours in 5% CO2 to carry out CCK-8 assay.
CCK-8 detection
Serum-free culture medium and CCK-8 solution are taken to prepare CCK-8 working solution according to the proportion of 10:1 (the process needs to be protected from light).
The cells cultured for 72 hours were removed from the incubator, the culture medium was aspirated from the well plate, and 120. mu. LCCK-8 working solution was added to each well, and 120. mu. LCCK-8 working solution was added to the cell-free well plate as a blank, and the cell-free well plate was incubated at 37 ℃ in a 5% CO2 incubator for 1 hour (this process required protection from light).
The plates were removed from the incubator and 100. mu.L of solution was pipetted into each well of a new 96-well plate and the absorbance read at 450nm (the process required protection from light).
Data processing:
tx: absorbance of the compound measured 72 hours after the compound was exposed to CCK-8
C: the absorbance of the negative control wells measured by CCK-8 after 72 hours of incubation
B: absorbance measured in blank control well, CCK-8
Examples 1-26 pyrrole amides 1-26 prepared using the compounds of formula I of this invention were run in the above assay and the results are shown in Table 3, where the highest IC50 of the one or more runs of each compound determined is classified as indicated in Table 3:
"+" indicates that the compound had an IC50 assay of greater than 10 μ M in cancer cells;
"+ +" indicates that the IC50 assay of the compound in cancer cells was less than 10. mu.M;
TABLE 3 inhibitory Activity of Pyrrolinamide Compounds 1-26 on different hepatocarcinoma cells
Test results show that the pyrrole amide compounds 1-26 prepared by the compound of the formula I have good inhibitory activity on different liver cancer cells (HepG2, Huh-7, Li-7 and Hep3B) and have a prospect of clinical application.
In conclusion, the pyrrole amide compound prepared by the compound shown in the formula I has the advantages of short process route, simple and convenient operation, high production efficiency, low energy consumption, safety and environmental protection, and the pyrrole amide compound with good deacetylase inhibitory activity can be conveniently obtained.
Claims (18)
1. An intermediate compound for preparing pyrrole amide compounds, wherein the intermediate compound is shown as a formula II, a formula III, a formula VI or a formula V:
wherein,
R1、R2and R3Selected from hydrogen;
R5selected from hydrogen, hydroxy, cyanoRadical, halogen, carboxyl, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6A heterocyclic group of (a) or a phenoxy group;
R6selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6A heterocyclic group of (a), a phenoxy group, a phenyl group or a substituted phenyl group;
x is selected fromA group, m ═ 0, 1,2 or 3, n ═ 0, 1 or 2;
R7selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6Heterocyclyl, phenoxy, phenyl, substituted phenyl;
R8、R9independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6A heterocyclic group of (a), a phenoxy group, a phenyl group, a substituted phenyl group.
2. The intermediate compound of claim 1, wherein:
R1、R2、R3independently or simultaneously selected from hydrogen;
R5selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, acetylamino, n-propionamido, isopropionylAmino, n-butylamido, iso-butylamido, tert-butylamido, pentanamido, hexanamido, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6A nitrogen heterocyclic group of (a) or a phenoxy group;
R6selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, acetylamino, n-propionamido, isopropanolamimido, n-butylamido, isobutanoylamino, tert-butylamido, pentanamido, hexanoylamino, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6A nitrogen heterocyclic group of (a), a phenoxy group, a phenyl group or a substituted phenyl group;
m is 1 or 2, n is 1 or 2;
R7selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, acetylamino, n-propionamido, isopropanolamimido, n-butylamido, isobutanoylamino, tert-butylamido, pentanamido, hexanoylamino, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Azaheterocyclyl, phenoxy, phenyl, substituted phenyl;
R8、R9independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, formamido, acetamido, n-propionamido, isopropamido, n-butylamido, isobutoxyAcylamino, tert-butyramido, pentanamido, hexanamido, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6A nitrogen heterocyclic group of (a), a phenoxy group, a phenyl group, a substituted phenyl group.
3. The intermediate compound of claim 2, wherein: the intermediate compound is:
4. a process for the preparation of the intermediate compound IM according to claim 3, characterized in that: the synthetic route is as follows:
wherein, Boc represents tert-butyloxycarbonyl; TFA represents trifluoroacetic acid; Fmoc-Cl represents fluorenylmethoxycarbonyl chloride; HATU stands for 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; DIEA represents N, N-diisopropylethylamine;
a. stirring a mixed solvent of a compound IM-4, lithium hydroxide and an ether solvent/water at the temperature of 20-30 ℃ for reaction for 1-6 h, removing the organic solvent, adding water for dilution, adjusting the pH value to 3-6, precipitating a solid, and filtering to obtain a solid; washing and drying the solid to obtain N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid;
the molar ratio of the compound IM-4 to the lithium hydroxide is 1: 1-10; the mass-volume ratio of the compound IM-4 to the mixed solvent is 1: 7-20 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
b. at the temperature of 0-5 ℃, dissolving the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid obtained in the step a in a halohydrocarbon solvent, adding trifluoroacetic acid, and stirring and reacting at the temperature of 20-30 ℃ for 2-12H to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-3;
the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the halohydrocarbon solvent is 1: 5-20 g/ml; the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the trifluoroacetic acid is 1: 2-10 g/ml;
c. b, stirring the compound IM-3 obtained in the step b, sodium carbonate, fluorenyloxycarbonyl chloride and a mixed solvent of an ether solvent and water at the temperature of 20-30 ℃ for reaction for 12-16 h, adding water for dilution, adjusting the pH value to 1-3, extracting by using the ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a compound IM-2;
the molar ratio of the compound IM-3, sodium carbonate and fluorenyloxycarbonyl chloride is 1: 1-5: 0.9 to 1.5; the mass-volume ratio of the compound IM-3 to the mixed solvent is 1: 10-25 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
d. c, stirring and reacting the compound IM-2, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at the temperature of 25-30 ℃ for 12-16H, adding water for diluting, extracting with an ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-1;
the molar ratio of the compound IM-2, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 1-2: 1-2: 2-4; the mass-volume ratio of the compound IM-2 to the halocarbon solvent is 1: 9-20 g/ml;
e. d, stirring the compound IM-1, piperidine and the nitrogen-containing solvent in the step d at 25-30 ℃ for reaction for 4-6 h, adding water for dilution, extracting by using an ester solvent, combining organic phases, and drying, filtering and concentrating the organic phases to obtain a compound IM;
the mass-to-volume ratio of the compound IM-1 to piperidine is 1: 1-4 g/ml; the mass volume ratio of the compound IM-1 to the nitrogen-containing solvent is 1: 5-20 g/ml.
5. Process for the preparation of the intermediate compound IM according to claim 4, characterized in that: the method comprises the following steps:
a. stirring a mixed solvent of a compound IM-4, lithium hydroxide and an ether solvent/water at 25 ℃ for 2 hours, removing the organic solvent, adding water for dilution, adjusting the pH to be 5, precipitating a solid, and filtering to obtain a solid; washing and drying the solid to obtain N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid;
the molar ratio of the compound IM-4 to the lithium hydroxide is 1: 4.5-5; the mass-volume ratio of the compound IM-4 to the mixed solvent is 1: 10-12 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 2: 1;
b. at the temperature of 0 ℃, dissolving the N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid obtained in the step a into a halohydrocarbon solvent, adding trifluoroacetic acid, and stirring and reacting at the temperature of 25 ℃ for 2 hours to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-3;
the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the halohydrocarbon solvent is 1: 10 g/ml; the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the trifluoroacetic acid is 1: 4-5 g/ml;
c. b, stirring the compound IM-3 obtained in the step b, sodium carbonate, fluorenyloxycarbonyl chloride and a mixed solvent of an ether solvent and water at 25 ℃ for 12-16 h, adding water for diluting, adjusting the pH value to 1, extracting by using an ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a compound IM-2;
the molar ratio of the compound IM-3, sodium carbonate and fluorenyloxycarbonyl chloride is 1: 3: 1; the mass-volume ratio of the compound IM-3 to the mixed solvent is 1: 20 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 5: 3;
d. c, stirring and reacting the compound IM-2, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at 25 ℃ for 12-16H, adding water for diluting, extracting with an ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-1;
the molar ratio of the compound IM-2, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 1.1: 1.2: 3; the mass-volume ratio of the compound IM-2 to the halocarbon solvent is 1: 9-10 g/ml;
e. d, stirring the compound IM-1, piperidine and the nitrogen-containing solvent in the step d at 25 ℃ for reacting for 4-6 h, adding water for diluting, extracting by using an ester solvent, combining organic phases, and drying, filtering and concentrating the organic phases to obtain a compound IM;
the mass-to-volume ratio of the compound IM-1 to piperidine is 1: 2 g/ml; the mass volume ratio of the compound IM-1 to the nitrogen-containing solvent is 1: 10 g/ml.
6. Process for the preparation of the intermediate compound IM according to claim 4 or 5, characterized in that: in the steps a to e, the ether solvent is one or more of tetrahydrofuran, diethyl ether, tert-butyl methyl ether, isopropyl ether and butyl ether; the halocarbon solvent is any one or more of dichloromethane, chloroethane, dichloroethane, trichloromethane and carbon tetrachloride; the ester solvent is one or more of ethyl acetate and ethyl formate; the nitrogen-containing solvent is one or more of N, N-dimethylformamide, N-dimethylacetamide, acetonitrile and pyridine.
7. A process for the preparation of an intermediate compound, characterized in that: the synthetic route is as follows:
or,
or
R5Selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6A heterocyclic group of (a) or a phenoxy group;
R6selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6A heterocyclic group of (a), a phenoxy group, a phenyl group or a substituted phenyl group;
x is selected fromA group, m ═ 0, 1,2 or 3, n ═ 0, 1 or 2;
R7selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6Heterocyclyl, phenoxy, phenyl, substituted phenyl;
R8、R9independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6Heterocyclyl, phenoxy, phenyl, substituted phenyl;
R10selected from halogens;
the method comprises the following steps:
①, compound IM, prepared according to the process of any one of claims 4 or 5;
②, compound IM of step ①, triethylamine,Reacting with halohydrocarbon solvent at 25-30 deg.c for 1-10 hr while stirring, and eliminating solvent to obtain coarse product; purifying the crude product by column chromatography to obtain a compound TM-1 (a); the compound IM, triethylamine,In a molar ratio of 1: 1-5: 1-2; the mass-volume ratio of the compound IM to the halocarbon solvent is 1: 50-100 g/ml;
or,
compound IM of step ①, triethylamine,Reacting with halohydrocarbon solvent at 25-30 deg.c for 1-10 hr while stirring, and eliminating solvent to obtain coarse product; purifying the crude product by column chromatography to obtain a compound TM-1 (b); the compound IM, triethylamine,In a molar ratio of 1: 1-5: 1-2; the mass-volume ratio of the compound IM to the halocarbon solvent is 1: 50-100 g/ml;
or,
compound IM of step ①, triethylamine,Reacting with halohydrocarbon solvent at 25-30 deg.c for 1-10 hr while stirring, and eliminating solvent to obtain coarse product; purifying the crude product by column chromatography to obtain a compound TM-1 (c); the chemical conversionCompound IM, triethylamine,In a molar ratio of 1: 1-5: 1-2; the mass-volume ratio of the compound IM to the halocarbon solvent is 1: 50-100 g/ml.
8. A process for the preparation of the intermediate compound according to claim 7, characterized in that: comprises the following steps
①, compound IM, prepared according to the process of any one of claims 4 or 5;
②, compound IM of step ①, triethylamine,Reacting with halohydrocarbon solvent at 25 deg.C under stirring for 2 hr, and removing solvent to obtain crude product; purifying the crude product by column chromatography to obtain a compound TM-1 (a); the compound IM, triethylamine,In a molar ratio of 1: 1.4: 1 to 1.2; the mass-volume ratio of the compound IM to the halocarbon solvent is 1: 80 g/ml;
or,
compound IM of step ①, triethylamine,Reacting with halohydrocarbon solvent at 25 deg.C under stirring for 2 hr, and removing solvent to obtain crude product; purifying the crude product by column chromatography to obtain a compound TM-1 (b); the compound IM, triethylamine,In a molar ratio of 1: 1.4: 1 to 1.2; the mass-volume ratio of the compound IM to the halocarbon solvent is 1: 80 g/ml;
or,
compound IM of step ①, triethylamine,Reacting with halohydrocarbon solvent at 25 deg.C under stirring for 2 hr, and removing solvent to obtain crude product; purifying the crude product by column chromatography to obtain a compound TM-1 (c); the compound IM, triethylamine,In a molar ratio of 1: 1.4: 1 to 1.2; the mass-volume ratio of the compound IM to the halocarbon solvent is 1: 80 g/ml.
9. A process for the preparation of the intermediate compound according to claim 7, characterized in that:
R5selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, acetylamino, n-propionamido, isopropanolamimido, n-butylamido, isobutanoylamino, tert-butylamido, pentanamido, hexanoylamino, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6A nitrogen heterocyclic group of (a) or a phenoxy group;
R6selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, acetylamino, n-propionamido, isopropanolamimido, n-butylamido, isobutanoylamino, tert-butylamido, pentanamido, hexanoylamino, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6A nitrogen heterocyclic group of (a), a phenoxy group, a phenyl group or a substituted phenyl group;
m is 1 or 2, n is 1 or 2;
R7selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, acetylamino, n-propionamido, isopropanolamimido, n-butylamido, isobutanoylamino, tert-butylamido, pentanamido, hexanoylamino, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Azaheterocyclyl, phenoxy, phenyl, substituted phenyl;
R8、R9independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamido, acetamido, n-propionamido, isopropamide, n-butylamido, isobutylamide, tert-butyramido, pentanamido, hexanamide, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Azaheterocyclyl, phenoxy, phenyl, substituted phenyl;
R10selected from fluorine, chlorine, bromine or iodine.
10. A process for the preparation of the intermediate compound according to claim 8, characterized in that:
R5selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, acetylamino, n-propionamido, isopropanolamimido, n-butylamido, isobutanamido, tert-butylamido, pentanamido, hexylcarboxamide, and the likeAlkanoylamino group, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6A nitrogen heterocyclic group of (a) or a phenoxy group;
R6selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, acetylamino, n-propionamido, isopropanolamimido, n-butylamido, isobutanoylamino, tert-butylamido, pentanamido, hexanoylamino, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6A nitrogen heterocyclic group of (a), a phenoxy group, a phenyl group or a substituted phenyl group;
m is 1 or 2, n is 1 or 2;
R7selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, acetylamino, n-propionamido, isopropanolamimido, n-butylamido, isobutanoylamino, tert-butylamido, pentanamido, hexanoylamino, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Azaheterocyclyl, phenoxy, phenyl, substituted phenyl;
R8、R9independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamido, acetamido, n-propionamido, isopropamide, n-butylamido, isobutylamide, tert-butyramido, pentanamido, hexanamide, C3Nitrogen ofHeterocyclic group, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Azaheterocyclyl, phenoxy, phenyl, substituted phenyl;
R10selected from fluorine, chlorine, bromine or iodine.
11. A process for the preparation of the intermediate compounds according to claim 9 or 10, characterized in that: the above-mentionedComprises the following steps:
12. the method for preparing intermediate compound according to claim 7, wherein in step ②, the halocarbon solvent is any one or more of dichloromethane, chloroethane, dichloroethane, chloroform, and carbon tetrachloride.
13. The method for preparing intermediate compound according to claim 8, wherein in step ②, the halocarbon solvent is any one or more of dichloromethane, chloroethane, dichloroethane, chloroform, and carbon tetrachloride.
14. A method for preparing pyrrole amide compounds by using intermediate compounds is characterized in that: the synthetic route is as follows:
or,
or,
R5selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6A heterocyclic group of (a) or a phenoxy group;
R6selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6A heterocyclic group of (a), a phenoxy group, a phenyl group or a substituted phenyl group;
x is selected fromA group, m ═ 0, 1,2 or 3, n ═ 0, 1 or 2;
R7selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6Heterocyclyl, phenoxy, phenyl, substituted phenyl;
R8、R9independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6Heterocyclyl, phenoxy, phenyl, substituted phenyl;
the method comprises the following steps:
i. preparing an intermediate compound TM-1(a) or TM-1(b) or TM-1(c) according to the process of claim 7;
ii. Dissolving the compound TM-1(a) in the step i in a halohydrocarbon solvent at 0-5 ℃, adding trifluoroacetic acid, stirring and reacting at 25-30 ℃ for 1-12 h, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (a); the mass-volume ratio of the compound TM-1(a) to the halocarbon solvent is 1: 50-100 g/ml; the mass-to-volume ratio of the compound TM-1(a) to trifluoroacetic acid is 1: 10-50 g/ml;
or,
dissolving the compound TM-1(b) in the step i in a halohydrocarbon solvent at 0-5 ℃, adding trifluoroacetic acid, stirring and reacting at 25-30 ℃ for 1-12 h, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (b); the mass-volume ratio of the compound TM-1(b) to the halocarbon solvent is 1: 50-100 g/ml; the mass-to-volume ratio of the compound TM-1(b) to trifluoroacetic acid is 1: 10-50 g/ml;
or,
dissolving the compound TM-1(c) in the step i in a halohydrocarbon solvent at 0-5 ℃, adding trifluoroacetic acid, stirring and reacting at 25-30 ℃ for 1-12 h, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (c); the mass-volume ratio of the compound TM-1(c) to the halocarbon solvent is 1: 50-100 g/ml; the mass-to-volume ratio of the compound TM-1(c) to trifluoroacetic acid is 1: 10-50 g/ml.
15. A method for preparing pyrrole amide compounds by using intermediate compounds is characterized in that: the synthetic route is as follows:
or,
or,
R5selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6A heterocyclic group of (a) or a phenoxy group;
R6selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6A heterocyclic group of (a), a phenoxy group, a phenyl group or a substituted phenyl group;
x is selected fromA group, m ═ 0, 1,2 or 3, n ═ 0, 1 or 2;
R7selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6Heterocyclyl, phenoxy, phenyl, substituted phenyl;
R8、R9independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C3～C6Heterocyclyl, phenoxy, phenyl, substituted phenyl;
the method comprises the following steps:
i. preparing an intermediate compound TM-1(a) or TM-1(b) or TM-1(c) according to the process of claim 8;
ii. Dissolving the compound TM-1(a) in the step i in a halohydrocarbon solvent at 0-5 ℃, adding trifluoroacetic acid, stirring and reacting at 25-30 ℃ for 1-12 h, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (a); the mass-volume ratio of the compound TM-1(a) to the halocarbon solvent is 1: 50-100 g/ml; the mass-to-volume ratio of the compound TM-1(a) to trifluoroacetic acid is 1: 10-50 g/ml;
or,
dissolving the compound TM-1(b) in the step i in a halohydrocarbon solvent at 0-5 ℃, adding trifluoroacetic acid, stirring and reacting at 25-30 ℃ for 1-12 h, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (b); the mass-volume ratio of the compound TM-1(b) to the halocarbon solvent is 1: 50-100 g/ml; the mass-to-volume ratio of the compound TM-1(b) to trifluoroacetic acid is 1: 10-50 g/ml;
or,
dissolving the compound TM-1(c) in the step i in a halohydrocarbon solvent at 0-5 ℃, adding trifluoroacetic acid, stirring and reacting at 25-30 ℃ for 1-12 h, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (c); the mass-volume ratio of the compound TM-1(c) to the halocarbon solvent is 1: 50-100 g/ml; the mass-to-volume ratio of the compound TM-1(c) to trifluoroacetic acid is 1: 10-50 g/ml.
16. The process for producing a pyrrole amide compound according to claim 14 or 15, wherein: the method comprises the following steps:
i. preparing an intermediate compound TM-1(a) or TM-1(b) or TM-1(c) according to the process of claim 7;
ii. Dissolving the compound TM-1(a) in the step i in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, stirring at 25 ℃ for reacting for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (a); the mass-volume ratio of the compound TM-1(a) to the halocarbon solvent is 1: 60-65 g/ml; the mass-to-volume ratio of the compound TM-1(a) to trifluoroacetic acid is 1: 25 g/ml;
or,
dissolving the compound TM-1(b) in the step i in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, stirring at 25 ℃ for reacting for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (b); the mass-volume ratio of the compound TM-1(b) to the halocarbon solvent is 1: 60-65 g/ml; the mass-to-volume ratio of the compound TM-1(b) to trifluoroacetic acid is 1: 25 g/ml;
or,
dissolving the compound TM-1(c) in the step i in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, stirring at 25 ℃ for reacting for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (c); the mass-volume ratio of the compound TM-1(c) to the halocarbon solvent is 1: 60-65 g/ml; the mass-to-volume ratio of the compound TM-1(c) to trifluoroacetic acid is 1: 25 g/ml.
17. The process for producing a pyrrole amide compound according to claim 14 or 15, wherein: the method comprises the following steps:
i. preparing an intermediate compound TM-1(a) or TM-1(b) or TM-1(c) according to the process of claim 8;
ii. Dissolving the compound TM-1(a) in the step i in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, stirring at 25 ℃ for reacting for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (a); the mass-volume ratio of the compound TM-1(a) to the halocarbon solvent is 1: 60-65 g/ml; the mass-to-volume ratio of the compound TM-1(a) to trifluoroacetic acid is 1: 25 g/ml;
or,
dissolving the compound TM-1(b) in the step i in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, stirring at 25 ℃ for reacting for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (b); the mass-volume ratio of the compound TM-1(b) to the halocarbon solvent is 1: 60-65 g/ml; the mass-to-volume ratio of the compound TM-1(b) to trifluoroacetic acid is 1: 25 g/ml;
or,
dissolving the compound TM-1(c) in the step i in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, stirring at 25 ℃ for reacting for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound TM (c); the mass-volume ratio of the compound TM-1(c) to the halocarbon solvent is 1: 60-65 g/ml; the mass-to-volume ratio of the compound TM-1(c) to trifluoroacetic acid is 1: 25 g/ml.
18. The process for producing a pyrrole amide compound according to claim 14 or 15, wherein: in step ii, the halocarbon solvent is any one or more of dichloromethane, chloroethane, dichloroethane, trichloromethane and carbon tetrachloride.
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| WO2010014054A1 (en) * | 2008-07-28 | 2010-02-04 | The Regents Of The University Of California | Inhibitors of protein prenyltransferases |
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