CN101195601A - 2-dihydro indolone derivant, preparation method and application thereof - Google Patents

2-dihydro indolone derivant, preparation method and application thereof Download PDF

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CN101195601A
CN101195601A CNA200610098202XA CN200610098202A CN101195601A CN 101195601 A CN101195601 A CN 101195601A CN A200610098202X A CNA200610098202X A CN A200610098202XA CN 200610098202 A CN200610098202 A CN 200610098202A CN 101195601 A CN101195601 A CN 101195601A
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methyl
tetrahydro
oxo
indole
hydrogen
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唐锋
沈晗
卢是玥
杨洁
殷晓进
丁磊
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Jiangsu Simcere Pharmaceutical R&D Co Ltd
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Jiangsu Simcere Pharmaceutical R&D Co Ltd
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Priority to CNA200610098202XA priority Critical patent/CN101195601A/en
Priority to ES07817351T priority patent/ES2383084T3/en
Priority to CN200780006890.5A priority patent/CN101389624B/en
Priority to PCT/CN2007/071161 priority patent/WO2008067756A1/en
Priority to US12/517,351 priority patent/US8084621B2/en
Priority to JP2009539592A priority patent/JP5542445B2/en
Priority to EP07817351A priority patent/EP2123649B1/en
Priority to AT07817351T priority patent/ATE547411T1/en
Publication of CN101195601A publication Critical patent/CN101195601A/en
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Abstract

The invention relates to a 2-dihydroindolone compound as formula (I), and a relative application of the compound or the medical acceptable salt of the compound. Pharmacological experiment proves that the compound or relative medical acceptable salt can restrain various cancer cell proliferations. The invention further relates to a preparation method of the compound and an intermediate formula (II) of the compound.

Description

2-indolinone derivative and preparation method and application thereof
Technical Field
The invention relates to a 2-indolinone compound with a structure shown in a formula (I) and application thereof. Pharmacological experiments show that the compounds have an inhibiting effect on the proliferation of various tumor cells. The invention also relates to a preparation method of the compound and an intermediate of the compound.
Background
The following is provided as background information only and is not considered prior art to the present invention.
Mammalian cells have similar molecular mechanisms that regulate cell proliferation, differentiation and death throughout the cell cycle. Among them, protein phosphorylation is a major mechanism of transmembrane or intracellular signal transduction, and has a function of regulating the cell cycle, and the phosphorylation is controlled by Protein Kinases (PKs) and protein phosphatases. Protein kinases are the largest family of proteins known to date, all of which have a very conserved catalytic core and diverse regulatory patterns. The role of protein kinases is to transfer the gamma phosphate group of ATP to specific amino acid residues on their substrates. These kinases are classified into 4 classes based on the specificity of these amino acid residues, the two major classes of which are protein serine/threonine kinases (STKs) and Protein Tyrosine Kinases (PTKs). In eukaryotes, there is physical separation and distance between the receptors on the cell surface and the transcription system in the nucleus, and extracellular signals influence the cascade of certain protein kinases through the receptors, and through the phosphorylation of multi-step proteins, the activity of transcription factors is finally changed, so that the transcription of genes is activated or blocked. Among them, protein tyrosine kinase and protein serine/threonine kinase play an important role in the signal transduction mechanism of normal cells, and their abnormal expression will lead to the generation of many diseases, such as tumor, arteriosclerosis, psoriasis, inflammatory reaction, etc., so that the regulation of the activity of these kinases to restore physiological equilibrium can be used as a new therapeutic means.
The tyrosine kinase family is widely involved in cell signal transduction as transmembrane receptors (receptor tyrosine kinases, RTKs) or cytoplasmic forms (non-receptor tyrosine kinases, CTKs). In the human genome, the protein kinase group includes 30 tyrosine kinase families, which contain 90 different protein tyrosine kinases, of which 58 are receptor tyrosine kinases. For a more detailed discussion of tyrosine kinases, see Manning G, Science, 2002, 298: 1912, which includes any drawings in their entirety as a whole, are incorporated herein by reference. Receptor tyrosine kinases are a class of transmembrane proteins with a cytoplasmic domain, an extracellular domain is a ligand domain, and ligands are soluble or membrane-bound polypeptides or protein-like hormones, including insulin and various growth factors. The intracellular segment is the catalytic site of protein tyrosine kinases and has an autophosphorylation site, in which catalytic activity is activated upon binding of a ligand. The receptors mainly include EGFR (epidermal growth factor receptor), VEGFR (vascular endothelial growth factor receptor), PDGFR (platelet-derived growth factor receptor), FGFR (fibroblast growth factor receptor), and the like. The most important downstream signaling cascades are activated by RTKs, including the ERK/MAPK signaling pathway, the PI-3 kinase-AKT signaling pathway, and the JAK/STAT signaling pathway. PTKs maintain mutual signaling in all of these different transduction pathways, ultimately regulating gene transcription. In addition, other cascades may be used. The regulatory mechanisms of non-receptor PTKs are widely divergent and they participate in extracellular signaling responses by physically interacting with transmembrane receptors (Grosios k, ethanol, Drugs Fut, 2003, 28: 679).
With the intensive research of molecular biology, the regulation of the function of growth factors and the regulation of oncogenes for cell signal transduction at the molecular level is an effective way to inhibit cell proliferation and treat tumors. This pathway can attenuate the effects of abnormal signaling pathways, prevent tumor growth, and also promote tumor cell death. It has been discovered to date that half of proto-oncogenes have PTK structures in protein coding, which are involved in cell signaling through phosphorylation and dephosphorylation, while mutated or overexpressed PTKs can convert normal cells into cancer cells during tumorigenesis, while promoting tumor cell growth and mitosis.
At the same time, both the growth and metastasis of the malignancy must pass through the peripheral neovasculature to continue to provide adequate nutrition. The process of angiogenesis in tumors can be roughly divided into two stages, namely, a pre-vascular stage and a vascular stage, and the transformation of the two stages is called an angiogenic switch. The transition of tumor cells to the angiogenic phenotype plays a key role in the process of tumor malignancy: when no angiogenesis exists around, the tumor cells can not obtain enough nutrients and can not discharge metabolites, the tumor cells mainly depend on oxygen and nutrient substances dispersed around the cells to live, and the tumor can only grow to the diameter of 1-2 mm; however, once transformed to the angiogenic phenotype, avascular tumors can rapidly grow using nutrients in their blood, and these malignant cells can cause phenotypic changes in other cells, such as endothelial cells, etc., which in turn promote neovascularization. Angiogenic factors regulate angiogenic switches, causing endothelial cell migration, proliferation and morphological changes, resulting in tumor vessels, and all currently known angiogenic factors are primarily ligands for PTKs, such as VEGF, bFGF, PD-ECGF, etc. (Bergers G, et al, Nat Rev Cancer, 2003, 3: 401). Thus, prevention of tumor angiogenesis is also an effective way to control the growth of malignant tumors using tyrosine kinase inhibitors as anti-angiogenic substances.
Tyrosine kinase inhibitors are particularly suitable for the treatment of tumors, since they play an important role in the oncogenic transformation of cells and are directly or indirectly linked to the generation and development of tumors.
Furthermore, like non-receptor PTKs, STKs predominate intracellularly, although there are only a few STK-type receptor kinases. STKs are the most common cytosolic kinases; i.e., the kinases exert their functions within the cytoplasmic portion rather than within the cytoplasmic organelles and cytoskeleton. The cytosol is a region within the cell where most cells undergo intermediary metabolism and biosynthesis.
In summary, PTKs and STKs are all clearly associated with pathological conditions of the host, including cancer. Other pathological conditions associated with PKs also include, but are not limited to, psoriasis, cirrhosis, diabetes, angiogenesis, restenosis, ophthalmic diseases, rheumatoid arthritis and other inflammatory diseases, immune diseases, cardiovascular diseases such as arteriosclerosis, and various renal diseases.
At present, attempts have been made to identify 2-indolinone type small molecule compounds as PK inhibitors, such as indirubin compounds (pctwoo 2001037819, pctwoo 2002092079), 3-methylenepyrrole-2-indolinone compounds (US6642251, PCT WO2001060814, PCT WO2003035009, PCT WO2005053686) and 3-pyrrolocyclopentylidene-2-indolinone compounds (PCT WO2005016875) and other 2-indolinone compounds (pco 2000012084), all of which are described as STK and/or PTK inhibitors for the treatment of cancer.
Disclosure of Invention
The present invention relates to novel 2-indolinone derivatives which exhibit an inhibitory activity against the proliferation of tumor cells. Furthermore, the present invention relates to a process for the preparation of the disclosed compounds and intermediates thereof.
The terms "2-indolinone," "2-oxindole," and "2-oxoindole," used interchangeably herein, refer to molecules having the following chemical structure.
Figure A20061009820200081
"Pyrrolocyclohexylene" refers to a molecule having the following chemical structure.
Figure A20061009820200082
"3-pyrrolocyclohexylidene-2-indolinone" refers to a compound having the general structure shown in formula (I).
"Pyrrolocyclohexanone" refers to a compound having the general structure shown in formula (II).
"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) salification with an acid, obtained by reaction of the free base of the parent compound with an inorganic or organic acid, such as (but not limited to) hydrochloric, hydrobromic, nitric, phosphoric, metaphosphoric, sulfuric, sulfurous, perchloric and the like, or with an organic acid, such as (but not limited to) acetic, propionic, acrylic, oxalic, (D) or (L) malic, fumaric, maleic, hydroxybenzoic, gamma-hydroxybutyric, methoxybenzoic, phthalic, methanesulfonic, ethanesulfonic, naphthalene-1-sulfonic, naphthalene-2-sulfonic, p-toluenesulfonic, salicylic, tartaric, citric, lactic, mandelic, succinic or malonic acid, and the like, preferably with hydrochloric or (L) malic acid
(2) The acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or is complexed with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.
1. Chemistry
The present invention relates to compounds having the following chemical structure:
Figure A20061009820200083
wherein:
R1is hydrogen, halogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, -C (O) R7、-NRR8R9、-(CH2)nR10or-C (O) NR11R12；
R2Is hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy, cyano, -NR8R9、-NR8C(O)R9、-C(O)R7Aryl, heteroaryl, -S (O)2NR8R9or-SO2R13；
R3Is hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy, -C (O) R7、-NR8R9Aryl, heteroaryl, -NR8S(O)2R9、-S(O)2NR8R9、-NR8C(O)R9、-NR8C(O)OR9or-SO2R13；
R4Is hydrogen, halogen, alkyl, hydroxy, alkoxy or-NR8R9；
R5Is hydrogen, alkyl or-C (O) R14；
R6Is hydroxy, alkoxy, aryloxy, -N (R)15)(CH2)rR16or-NR8R9；
R7Is hydrogen, hydroxy, alkoxy or aryloxy;
R10is hydroxy, -C (O) R7、-NR8R9or-C (O) NR8R9；
R11And R12Independently selected from hydrogen, alkylOr aryl, or R11And R12Together with the nitrogen atom to which they are attached form a heterocyclic group;
R13is alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
R14is hydroxy, alkoxy, aryloxy or-NR8R9；
R15Is hydrogen or alkyl;
R16is hydroxy, -NR8R9、-C(O)R7Aryl, heteroaryl, -N+(O-)R8R9、-N(OH)R8or-NHC (O) RaWherein R isaIs unsubstituted alkyl, haloalkyl or aralkyl;
R8and R9Independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R8 and R9 taken together form a heterocyclyl;
n and r are independently 1, 2, 3 or 4.
The compound as described above or a pharmaceutically acceptable salt thereof, wherein
R1、R3And R4Preferably hydrogen;
R2preferably hydrogen, halogen or alkyl;
R5preferably methyl;
R6preferably hydroxy, -NR8R9or-N (R)15)(CH2)rR16；
R15Preferably hydrogen;
R16preferably hydroxy or-NR8R9；
R8And R9Preferably hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R8And R9Taken together to form a heterocyclic group;
r is preferably 2 or 3.
A process for the preparation of a compound of formula (I) by reacting a compound of formula (III) with a compound of formula (II) in an aprotic solvent in the presence of a Lewis acid at a temperature of from 50 ℃ to 150 ℃ for a period of from 1 hour to 20 hours, according to the following equation:
Figure A20061009820200091
wherein R is1、R2、R3、R4、R5、R6Is as defined above.
The Lewis acid is AlCl3、BF3、SnCl4、SnCl2、ZnCl2Or TiCl4Preferably SnCl4Or TiCl4Most preferably TiCl4。
The aprotic solvent is aprotic solvent or inert solvent, wherein the aprotic solvent can be N, N-dimethylformamide, acetone, acetonitrile, dimethyl sulfoxide, pyridine, or inert solvent can be pentane, hexane, cyclohexane, benzene, toluene, preferably pyridine.
The above reaction temperature is preferably 85 ℃ to 120 ℃, most preferably 100 ℃ to 110 ℃.
The reaction time is preferably 5 to 13 hours, and most preferably 8 to 10 hours.
In the above-mentioned reaction, the reaction is carried out,
R1、R3and R4Preferably hydrogen;
R2preferably hydrogen, halogen, alkyl, trihalomethyl, hydroxy, alkoxy, cyano, -NR8R9、-NR8C(O)R9、-C(O)R7Aryl, heteroaryl, -S (O)2NR8R9or-SO2R13；
R5Preferably methyl;
R6preferably hydroxy, alkoxy or-N (R)15)(CH2)rR16；
R7Preferably hydrogen, hydroxy, alkoxy or aryloxy;
R13preferably alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
R15preferably hydrogen or alkyl;
R16preferably hydroxy or-NR8R9；
R8And R9Preferably hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R8 and R9 together form a heterocyclic group;
r is preferably 2 or 3.
The compound disclosed by the invention is applied to preparation of antitumor drugs.
An intermediate of formula (II):
Figure A20061009820200101
wherein:
R5is hydrogen, alkyl or-C (O) R14Preferably methyl;
R6is hydroxy, alkoxy, aryloxy, -N (R)15)(CH2)rR16or-NR8R9Preferably hydroxy, ethoxy or-N (R)15)(CH2)rR16；
R15Is hydrogen or alkyl;
R16is hydroxy, -NR8R9、-C(O)R7Aryl, heteroaryl, -N+(O-)R8R9、-N(OH)R8or-NHC (O) RaWherein R isaIs unsubstituted alkyl, haloalkyl or aralkyl; preferably hydroxy or-NR8R9；
R8And R9Independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R8And R9Taken together to form a heterocyclic group; r7Is hydrogen, hydroxy, alkoxy or aryloxy;
r is 1, 2, 3 or 4, preferably 2 or 3.
A. General structural features
The present invention relates to compounds having the structure of formula (I):
Figure A20061009820200111
wherein:
R1is hydrogen, halogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, -C (O) R7、-NR8R9、-(CH2)nR10or-C (O) NR11R12；
R2Is hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy, cyano, -NR8R9、-NR8C(O)R9、-C(O)R7Aryl, heteroaryl, -S (O)2NR8R9or-SO2R13；
R3Is hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy, -C (O) R7、-NR8R9Aryl, heteroaryl, -NR8S(O)2R9、-S(O)2NR8R9、-NR8C(O)R9、-NR8C(O)OR9or-SO2R13；
R4Is hydrogen, halogen, alkyl, hydroxy, alkoxy or-NR8R9；
R5Is hydrogen, alkyl or-C (O) R14；
R6Is hydroxy, alkoxy, aryloxy, -N (R)15)(CH2)rR16or-NR8R9；
R7Is hydrogen, hydroxy, alkoxy or aryloxy;
R10is hydroxy, -C (O) R7、-NR8R9or-C (O) NR8R9；
R11And R12Independently selected from hydrogen, alkyl or aryl, or R11And R12Together with the nitrogen atom to which they are attached form a heterocyclic group;
R13is alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
R14is hydroxy, alkoxy, aryloxy or-NR8R9；
R15Is hydrogen or alkyl;
R16is hydroxy, -NR8R9、-C(O)R7Aryl, heteroaryl, -N+(O-)R8R9、-N(OH)R8or-NHC (O) RaWherein R isaIs unsubstituted alkyl, haloalkyl or aralkyl;
R8and R9Independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl,or R8 and R9 taken together form a heterocyclic group;
n and r are independently 1, 2, 3 or 4.
Unless otherwise indicated, the following terms used in the specification and claims have the meanings discussed below:
"alkyl" means a saturated aliphatic radical of 1 to 20 carbon atoms, including straight and branched chain radicals (a numerical range referred to herein, e.g., "1 to 20", means that the radical, in this case alkyl, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). Alkyl groups having 1 to 4 carbon atoms are referred to as lower alkyl groups. When a lower alkyl group has no substituent, it is referred to as unsubstituted lower alkyl. More preferably, the alkyl group is a medium size alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, and the like. Preferably, the alkyl group is a lower alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, or the like. Alkyl groups may be substituted or unsubstituted. When substituted alkyl, the substituent is preferably one or more, more preferably 1 to 3, most preferably 1 or 2 substituents, independently preferably selected from the group consisting of: halogen, hydroxy, lower alkoxy, aryl, aryloxy, heteroaryl, heteroalicyclic, -C (O) R7，-NR8R9and-C (O) NR11R12Wherein R is7、R8、R9、R11And R12The definition is the same as above.
"cycloalkyl" means a monocyclic or fused ring all carbon (by "fused" ring is meant that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system) group in which one or more rings do not have a fully attached pi-electron system, examples of cycloalkyl (without limitation) being cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane, and cycloheptatriene. Cycloalkyl groups may be substituted and unsubstituted. When substituted, the substituents are preferably one or moreEach selected from the group consisting of: alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylmercapto, arylmercapto, cyano, halogen, carbonyl, thiocarbonyl, C-carboxy, O-carbamoyl, N-carbamoyl, C-acylamino, N-acylamino, nitro, amino and-NR8R9Wherein R is8And R9The definition is the same as above.
"aryl" means an all-carbon monocyclic or fused polycyclic group of 1 to 12 carbon atoms having a completely conjugated pi-electron system. Non-limiting examples of aryl groups are phenyl, naphthyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, even more preferably one or two, independently selected from the group consisting of lower alkyl, trihaloalkyl, halogen, hydroxy, lower alkoxy, mercapto, (lower alkyl) thio, cyano, acyl, thioacyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, nitro, N-sulfonamido, S-sulfonamido, R8S(O)-、R8S(O)2-、-C(O)OR8、R8C (O) O-and-NR8R9Group of R8And R9The definition is the same as above. Preferably, aryl is optionally substituted with one or two substituents independently selected from halogen, lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-acylamino, mono-or dialkylamino, carboxy or N-sulphonamido.
"heteroaryl" denotes a monocyclic or fused ring group of 5 to 12 ring atoms, containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C, and additionally having a completely conjugated pi-electron system. Non-limiting examples of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine and carbazole. Heteroaryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably oneOne, two or three, even more preferably one or two, are independently selected from the group comprising: lower alkyl, trihaloalkyl, halogen, hydroxy, lower alkoxy, mercapto, (lower alkyl) thio, cyano, acyl, thioacyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, nitro, N-sulphonylamino, S-sulphonylamino, R8S(O)-、R8S(O)2-、-C(O)OR8、R8C (O) O-and-NR8R9Wherein R is8And R9The definition is the same as above. Preferred heteroaryl groups are optionally substituted with one or two substituents independently selected from halogen, lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-acylamino, mono-or dialkylamino, carboxy or N-sulphonamido.
"Heteroalicyclic group" means a monocyclic or fused ring group having 5 to 9 ring atoms in the ring, wherein one or two ring atoms are selected from N, O or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are C. These rings may have one or more double bonds, but these rings do not have a completely conjugated pi-electron system. Non-limiting examples of unsubstituted heteroalicyclic groups are pyrrolidinyl, piperidino, piperazino, morpholino, thiomorpholino, homopiperazino, and the like. The heteroalicyclic group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, even more preferably one or two, independently selected from the group comprising: lower alkyl, trihaloalkyl, halogen, hydroxy, lower alkoxy, mercapto, (lower alkyl) thio, cyano, acyl, thioacyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, nitro, N-sulphonylamino, S-sulphonylamino, R8S(O)-、R8S(O)2-、-C(O)OR8、R8C (O) O-and-NR8R9Wherein R is8And R9The definition is the same as above. Preferably, the heteroalicyclic group is optionally substituted by one or twoAnd (b) is substituted with substituents independently selected from halogen, lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-acylamino, mono-or dialkylamino, carboxy or N-sulphonamido. .
"heterocycle" means a saturated cyclic group of 3 to 8 ring atoms in which one or two ring atoms are selected from N, O or S (O)m(wherein m is an integer from 0 to 2) and the remaining ring atoms are C, wherein one or two C atoms may optionally be replaced by a carbonyl group. The rings of the heterocyclic group may be optionally independently substituted with one, two or three substituents selected from lower alkyl (optionally substituted with one or two substituents independently selected from carboxy or ester groups), haloalkyl, halogen, nitro, cyano, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, aralkyl, heteroaralkyl and-COR (wherein R is alkyl). More specifically, the term heterocyclyl includes, but is not limited to, tetrahydropyranyl, 2-dimethyl-1, 3-dioxolane, piperidino, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl, pyrrolidinyl, morpholino, thiomorpholino-1-oxide, thiomorpholino-1, 1-dioxide, 4-ethoxycarbonylpiperazino, 3-oxopiperazino, 2-imidazolidinone, 2-pyrrolidone, 2-oxophomopiperazino, tetrahydropyrimidin-2-one, and derivatives thereof. Preferably, the heterocyclic group is optionally substituted with one or two substituents independently selected from halogen, lower alkyl substituted with carboxy or an ester group, hydroxy, mono-or dialkylamino.
"hydroxy" means an-OH group.
"alkoxy" means-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
"aryloxy" means-O-aryl and-O-heteroaryl. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furyloxy, thiophenyloxy, pyrimidyloxy, pyrazinyloxy, and the like, and derivatives thereof.
"mercapto" means an-SH group.
"acyl" represents a group-C (O) -R ', wherein R' is a group selected from: hydrogen, unsubstituted lower alkyl, trihalomethyl, unsubstituted cycloalkyl, optionally substituted by one or more, preferably by 1, 2 or 3 groups selected from unsubstituted lower alkyl, trihalomethyl, unsubstituted lower alkoxy, halogen and-NR8R9Aryl substituted by a substituent of the group, wherein R8And R9As defined above, optionally substituted by one or more, preferably by 1, 2 or 3 groups selected from unsubstituted lower alkyl, trihalomethyl, unsubstituted lower alkoxy, halogen and-NR8R9Heteroaryl substituted with a substituent of the group (bonded through a ring carbon atom), and optionally substituted with one or more, preferably with 1, 2 or 3 substituents selected from unsubstituted lower alkyl, trihalomethyl, unsubstituted lower alkoxy, halogen and-NR8R9Substituent groups of the group substituted heteroalicyclic (bonded through a ring carbon atom), representative acyl groups include, but are not limited to, acetyl, trifluoroacetyl, benzoyl and the like.
"Thioacyl" means a-C (S) -R 'group, wherein R' is as defined above.
"ester group" means a-C (O) O-R ' group, wherein R ' is as defined above, but R ' cannot be hydrogen.
"acetyl" means-C (O) CH3A group.
"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
"Trihalomethyl" means-CX3A radical in which X is halogen as defined above.
"cyano" means a-CN group.
"S-sulfonylamino" means-S (O)2NR8R9Group, wherein R8And R9The definition is the same as above.
"N-sulfonylamino" denotes-NR8S(O)2R9Group, wherein R8And R9The definition is the same as above.
"O-carbamoyl" means-OC (O) NR11R12Group, wherein R11And R12The definition is the same as above.
"N-carbamoyl" denotes R8OC(O)NR9A group in which R8And R9The definition is the same as above.
"O-thiocarbamoyl" means-OC (S) NR11R12Group, wherein R11And R12The definition is the same as above.
"N-thiocarbamoyl" denotes R8OC(S)NR9A group in which R8And R9The definition is the same as above.
"amino" means-NH2A group.
"C-acylamino" denotes-C (O) NR8R9Group, wherein R8And R9The definition is the same as above.
"N-acylamino" denotes R8C(O)NR9A group in which R8And R9The definition is the same as above.
"nitro" means-NO2A group.
"haloalkyl" denotes alkyl, preferably lower alkyl as defined above, substituted by one or more identical or different halogen atoms, e.g. -CH2Cl、-CF3、-CCl3、-CH2CF3、-CH2CCl3And the like.
"aralkyl" denotes alkyl, preferably lower alkyl as defined above, substituted by aryl as defined above, e.g. -CH2Phenyl, - (CH)2)2Phenyl, - (CH)2)3Phenyl radical, CH3CH(CH3)CH2Phenyl and its derivatives.
"Heteroaralkyl" denotes alkyl, preferably lower alkyl as defined above, substituted by heteroaryl, e.g. -CH2Pyridyl, - (CH)2)2Pyrimidinyl, - (CH)2)3Imidazolyl and the like and derivatives thereof.
"Monoalkylamino" represents the group-NHR, where R is alkyl as defined above or unsubstituted cycloalkyl, such as methylamino, (1-methylethyl) amino, cyclohexylamino, and the like.
"dialkylamino" represents a group-NRR where each R is independently an alkyl group as defined above or an unsubstituted cycloalkyl group, such as dimethylamino, diethylamino, N-methylcyclohexylamino, and the like.
"piperazino" refers to a group having the following chemical structure.
Figure A20061009820200141
"morpholino" refers to a group having the following chemical structure.
Figure A20061009820200142
"piperidino" refers to a group having the following chemical structure.
Figure A20061009820200151
"pyrrolidinyl" refers to a group having the following chemical structure.
Figure A20061009820200152
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heteroaryl is optionally substituted with one or two substituents" means that the substituents for heteroaryl can be, but need not be, one, and this description includes the case where heteroaryl is substituted with one substituent and the case where heteroaryl is substituted with two substituents.
B. Preferred constructional features
R1、R3、R4Is hydrogen is a preferred feature of the invention.
R2Is hydrogen, halogen or alkyl is a preferred feature of the invention.
R5Methyl is a preferred feature of the invention.
R6Is hydroxy or-NR8R9Is a preferred feature of the invention, or R6is-N (R)15)(CH2)rR16Are also a preferred feature of the invention. Wherein R is15Is hydrogen, R is 2 or 3, R16Is hydroxy or-NR8R9(R8And R9Preferably hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R8And R9Taken together to form a heterocyclic group), wherein-NR8R9Is preferably-N (CH)3)2、-N(CH2CH3)2Morpholino, piperazino, piperidino, pyrrolidino, or N-methyl-piperazino.
2. Synthesis and combinatorial libraries
A. Combined storehouse
One aspect of the invention is the reaction of a 2-hydroxyindole of formula (III) with a pyrrolocyclohexanone of formula (II) to form a combinatorial library of compounds having the structure of formula (I).
Wherein R is1、R2、R3、R4、R5And R6Have the meanings set forth in the general structure.
As used herein, a "combinatorial library" refers to all compounds formed in a multidimensional array of compounds by reacting each compound in one dimension with a compound in each of the other dimensions. In the context of the present invention, the array is two-dimensional and one dimension represents all 2-hydroxyindoles of the invention and the second dimension represents all pyrrolocyclohexanones of the invention. Each 2-hydroxyindole may be reacted with each pyrrolocyclohexanone to form a 3-pyrrolocyclohexylidene-2-indolinone compound of formula (I). All 3-pyrrolocyclohexylidene-2-indolinone compounds formed in this way are within the scope of the invention. Smaller combinatorial libraries formed by reacting some 2-hydroxyindole with all pyrrolocyclohexanone, all 2-hydroxyindole with some pyrrolocyclohexanone, or some 2-hydroxyindole with some pyrrolocyclohexanone are also within the scope of the present invention.
The 2-hydroxyindole in the above combinatorial library is preferably selected from the group consisting of 2-hydroxyindole itself and substituted 2-hydroxyindoles such as, but not limited to, 5-fluoro-2-indolinone, 5-chloro-2-indolinone, 5-bromo-2-indolinone, 5-hydroxy-2-indolinone, 5-methyl-2-indolinone, 5-ethyl-2-indolinone, 5-n-butyl-2-indolinone, 5-methoxy-2-indolinone, 5-ethoxy-2-indolinone, 5-amino-2-indolinone, 5-acetyl-2-indolinone, 5-hydroxy-2-indolinone, 5-chloro-2-indolinone, 5-bromo-2-indolinone, 5-hydroxy-2-indolinone, 5-methyl-2-indolinone, 5-ethyl-2-indoli, 5-phenylaminosulfonyl-2-indolinone, 5-aminosulfonyl-2-indolinone, 5-isopropylaminosulfonyl-2-indolinone, 5-dimethylaminosulfonyl-2-indolinone, 5-trifluoromethyl-2-indolinone, 6-fluoro-2-indolinone, 6-methoxy-2-indolinone, 6-methyl-2-indolinone, 6-chloro-2-indolinone, 4-methyl-5-chloro-2-indolinone, 4, 5-dimethoxy-2-indolinone.
The pyrrolocyclohexanone in the above combinatorial library is preferably selected from, but not limited to, 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid ethyl ester, N- (2-diethylaminoethyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide, N- (2-dimethylaminoethyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide, N- (2-hydroxyethyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide, 2-methyl-3- (4-methyl-piperazine-1-carbonyl) -7-oxo-4, 5, 6, 7-tetrahydro-1H-indole, 2-methyl-3- (morpholine-4-carbonyl) -7-oxo-4, 5, 6, 7-tetrahydro-1H-indole, N- [2- (piperidin-1-yl) -ethyl ] -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide, pharmaceutically acceptable salts thereof, solvates thereof, and pharmaceutical compositions containing said compounds, N- [2- (pyrrolidin-1-yl) -ethyl ] -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide, N- [2- (morpholin-4-yl) -ethyl ] -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide, N- [2- (4-methyl-piperazin-1-yl) -ethyl ] -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide, N- (3-dimethylaminopropyl) -2-methyl-7-oxo- 4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide, N- [3- (pyrrolidin-1-yl) -propyl ] -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide, N- [3- (piperidin-1-yl) -propyl ] -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide, N- [3- (morpholin-4-yl) -propyl ] -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide, pharmaceutically acceptable salts thereof, solvates thereof, and pharmaceutically acceptable salts thereof, N- [3- (4-methyl-piperazin-1-yl) -propyl ] -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide, N- (3-diethylaminopropyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide.
B. General synthetic methods
(1) Intermediate body type (II)
Intermediates involved in the inventionPyrrolocyclohexanones of formula (II) were synthesized according to the following route: refluxing 6-amino-5-oxohexanoic acid hydrochloride (S1) and ethyl acetoacetate in sodium dihydrogen phosphate water solution to obtain substituted pyrrole (S2), and reacting polyphosphoric acid (PPA) as reaction solvent and phosphorus pentoxide (P)2O5) Reacting at 70 deg.C to obtain 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid ethyl ester (S3) as dehydrating agent, hydrolyzing in 1mol/L aqueous solution of LiOH to obtain 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (S4), and reacting with HN (R) in the presence of condensing agent in the presence of N, N-Dimethylformamide (DMF) as solvent15)(CH2)rR16The reaction is carried out at room temperature for 24 hours to obtain the pyrrolocyclohexanone in the formula (II).
Figure A20061009820200161
Wherein the substituents are as described above, preferably:
R5is methyl;
R6is-N (R)15)(CH2)rR16Or R is6Is ethoxy (formula (S3)), or R6Is hydroxy (formula (S4));
R15is hydrogen or alkyl;
R16is hydroxy or-NR8R9；
R8And R9Independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R8 and R9 taken together form a heterocyclyl;
r is 2 or 3.
Condensing agents include, but are not limited to, N ' -Dicyclohexylcarbodiimide (DCC), N ' -Diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 2, 4-dichloro-6-methoxy-1.3.5-triazine (DCMT), 1 ' -Carbonyldiimidazole (CDI) and 1-hydroxybenzotriazole (HOBt), preferably EDCI and HOBt.
The reaction is carried out at room temperature, preferably at a reaction temperature of 20 ℃ to 25 ℃.
(2) A compound of formula (I)
The present invention provides a process (A) for the synthesis of 3-pyrrolocyclohexylidene-2-indolinone of formula (I) comprising reacting a 2-hydroxyindole of formula (III) with pyrrolocyclohexanone of formula (II) in a solvent in the presence of a Lewis acid, wherein the substituents are as described above, preferably:
R1、R3and R4Is hydrogen;
R2is hydrogen, halogen, alkyl, trihalomethyl, hydroxy, alkoxy, cyano, -NR8R9、-NR8C(O)R9、-C(O)R7Aryl, heteroaryl, -S (O)2NR8R9or-SO2R13；
R5Is methyl;
R6is hydroxy, alkoxy or-N (R)15)(CH2)rR16；
R7Is hydrogen, hydroxy, alkoxy or aryloxy;
R13is alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
R15is hydrogen or alkyl;
R16is hydroxy or-NR8R9；
R8And R9Independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R8 and R9 taken together form a heterocyclyl;
r is 2 or 3.
Figure A20061009820200171
Method (A)
The reaction may be carried out in the presence of a Lewis acid, including but not limited to AlCl3、BF3、SnCl4、SnCl2、ZnCl2、TiCl4In a preferred embodiment of the invention, the Lewis acid is preferably SnCl4And TiCl4Most preferably TiCl4。
The solvent in which the reaction is carried out is an aprotic solvent. An "aprotic solvent" is a solvent having no transfer protons in the molecule, and such solvents can be further classified into aprotic solvents and inert solvents. An "aprotic protic solvent" is characterized by the absence of protons in the molecule, by little acidity compared to water, or by the absence of amphoteric character, but has a weaker tendency to accept protons and a different degree of hydrogen bonding capability, examples include (but are not limited to) amides, ketones, nitriles, dimethylsulfoxide, pyridine. "inert solvents" have no acid-base properties or are very weak in acid-base properties, do not themselves undergo proton transfer processes, and when solute acids and bases react in a solvent, solvent molecules do not participate in the reaction, examples include (but are not limited to) pentane, hexane, cyclohexane, benzene, toluene.
In a preferred embodiment of the invention, the solvent is an aprotic solvent, preferably pyridine.
The reaction is carried out at a temperature above room temperature. The temperature is generally from 50 ℃ to 150 ℃, preferably from 85 ℃ to 120 ℃, most preferably from 100 ℃ to 110 ℃.
The reaction time of the reaction is 1 hour to 20 hours, preferably 5 hours to 13 hours, and most preferably 8 hours to 10 hours.
Another aspect of the present invention is to provideAnother process (B) is provided for the synthesis of 3-pyrrolocyclohexylidene-2-indolinone of formula (I). According to the reaction conditions of the method (A), 2-hydroxyindole of the formula (III) reacts with 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (S4) to obtain a compound with the structure shown in the formula (IV), and then the compound reacts with HNR in the presence of a condensing agent by taking N, N-Dimethylformamide (DMF) as a solvent8R9Reacting at room temperature for 24 hours, wherein R6is-NR8R9，R1、R2、R3、R4、R8And R9The definition is as shown in method (A).
Figure A20061009820200181
Method (B)
Condensing agents for the reaction include, but are not limited to, N ' -Dicyclohexylcarbodiimide (DCC), N ' -Diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 2, 4-dichloro-6-methoxy-1.3.5-triazine (DCMT), 1 ' -Carbonyldiimidazole (CDI), and 1-hydroxybenzotriazole (HOBt), with EDCI and HOBt being preferred.
In addition, the compound S1 of the present invention can be prepared according to the existing literature in the field, such as Lartillot, Serge. et al, Bulletin de la Societe Chimique de France, 1964, 4: 783; MacGee, j.et al. biochem Med, 1977, 17: 31; evans DA, et al, j.c.s.chem.comm, 1978, 17: 753 and related documents cited therein. Of the formula HNR8R9And HN (R)15)(CH2)rR16Are commercially available amines. The intermediates of formula (III) involved in the synthesis of process (A) provided by the present invention are commercially available or can be prepared by methods similar to those reported in the literature in the art, such as "Rodd's Chemistry ofCarbon Compounds second edition, S.Coffey, volume IV, part A, 1973, pp.448-450; gassman PG, et al, J Org Chem, 1977, 42: 1340; wright WB et al, JAm Chem Soc, 1956, 78: 221; kisteneva, ms. zhumal obshcei khimi, 1956, 26: 2251; BeckettAH, et al, Tetrahedron, 1968, 24: 6093; walker GN, J Am Chem Soc, 1955, 77: 3844; protiva M, et al, collection Czech Chem commu, 1979, 44: 2108; McEvoy FJ, et al, J Org Chem, 1973, 38: 3350; simet L, J Org Chem, 1963, 28: 3580; wieland T, et al, Chem be, 1963, 96: 253; US patents 3882236, 4006161 and 4160032 and the related documents to which they are cited.
Also, it will be appreciated by those skilled in the art that other synthetic routes for generating the compounds of the invention are available, and that the examples provided herein are by way of illustration and not of limitation.
3. Biological evaluation method
The cell proliferation inhibition assay employs the commonly used MTT method: dehydrogenases in the mitochondria of living cells are capable of reducing yellow brominated 3- (4, 5-dimethylthiazol-2) -2, 5-diphenyltetrazolium (MTT) to Formazan (Formazan), a blue-violet, water-insoluble Formazan, the amount of Formazan being known by measuring the absorbance (OD value) at 570nm using a microplate reader, and thus the Formazan yield is generally proportional to the number of living cells, and thus the number of living cells can be inferred from the OD value, and the ability of the drug to inhibit or kill cells can be understood.
This assay can be used to determine the ability of different compounds of the invention to inhibit the proliferation of one or more cancer cells, and similar assays can be used for any cancer cell using methods well known in the art.
Detailed Description
The following preparations and examples are given to enable those skilled in the art to more clearly understand and practice the present invention. They should not be construed as limiting the scope of the invention but merely as exemplifications and representations thereof.
Example 1: 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (S4)
Figure A20061009820200191
Step 1
6-amino-5-oxohexanoic acid hydrochloride (S1)22.44g (0.12mol) (Lartillot, Serge. et al, Bulletin de la society Chimie de France, 1964, 4: 783) was dissolved in about 6.1L sodium dihydrogen phosphate buffer (300g sodium dihydrogen phosphate solid was dissolved in 6L water and pH was adjusted to about 6.5 with 1mol/L aqueous NaOH), 16.12g (0.12mol) ethyl acetoacetate was added, the reaction was refluxed for half an hour at elevated temperature, after cooling, the reaction solution was Na-treated2CO3The pH was adjusted to about 8 and the mixture was extracted once with 100ml of chloroform, and the aqueous phase was adjusted to about 1 with 6mol/L hydrochloric acid to precipitate a large amount of brown solid, which was filtered and dried under vacuum to obtain 20.29g (71% yield) of 4- (4-ethoxycarbonyl-5-methyl-1H-pyrrol-3-yl) butanoic acid as a solid (S2).
1HNMR(500MHz，DMSO-d6)δ11.89(s，1H，-COOH)，10.90(s，1H，-NH-1)，6.38(s，1H，pyrrole-2)，4.14(q，2H，-CH 2 CH3)，2.56(t，2H，-CH 2 CH2CH2COOH)，2.36(s，3H，-CH3-5)，2.18(t，2H，-CH2CH2 CH 2 -COOH)，1.71(m，2H，-CH2 CH 2 CH2COOH)，1.25(t，3H，-CH2CH3).
Step 2
142g of polyphosphoric acid, 7.1g of phosphorus pentoxide were added, and stirred at 70 ℃ for 30 minutes, followed by addition of 6.3g (0.026mol) of 4- (4-ethoxycarbonyl-5-methyl-1H-pyrrole-3-yl) butyric acid (S2), at which temperature after a further 48 hours of stirring, was poured into ice water and saturated Na was added2CO3Adjusting pH of the aqueous solution to about 8, and extracting with ethyl acetate. The organic layer was washed with water and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, concentrated to remove most of the ethyl acetate to saturation, crystallized at-5 ℃ at low temperature, filtered, and dried under vacuum to obtain 3.5g (61%) of ethyl 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylate (S3) as a white solid.
1HNMR(500MHz，CDCl3)δ10.23(s，1H，-NH-1)，4.30(q，2H，-CH2CH3)，3.00(t，2H，-CH2-4)，2.59(s，3H，-CH3-2)，2.50(t，2H，-CH2-6)，2.12(m，2H，-CH2-5)，1.36(t，3H，-CH2 CH 3 )；
ESI-MS：222.1[M+H]+；220.1[M-H]-.
Step 3
To 25ml of an aqueous LiOH solution (1mol/L) was added 1.0g (4.5mmol) of ethyl 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylate (S3), and the mixture was reacted at 70 ℃ for 48 hours, poured into ice water, adjusted to pH 1 to 2 with 6mol/L hydrochloric acid, to precipitate a large amount of solid, filtered, washed with water, and dried under vacuum to obtain 0.64g (74%) of the title compound as a gray solid.
1HNMR(500MHz，DMSO-d6)δ12.03(bs，2H，-NH-1，-COOH)，2.87(t，2H，-CH2-4)，2.42(s，3H，-CH3-2)，2.34(t，2H，-CH2-6)，1.98(m，2H，-CH2-5)；
ESI-MS：194.1[M+H]+.
Example 2: n- (2-diethylaminoethyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (II-1)
Figure A20061009820200201
0.2g (1.0mmol) of 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (S4), 0.16g of HOBt (1.2mmol), 0.24g (1.2mmol) of EDCI and 0.2g (2.0mmol) of triethylamine are dissolved in 10ml of DMF and stirred at room temperature for 20min, 0.24g (2.1mmol) of N, N-diethyl-1, 2-ethylenediamine are added and stirred at room temperature for 24 hours, the reaction mixture is poured into ice water, extracted with dichloromethane, the organic layer is washed with water and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and the solid obtained by concentration is purified by silica gel column chromatography (eluent dichloromethane: methanol 30: 1) to obtain 0.23g (79%) of the title compound as a white solid.
1HNMR(500MHz，CDCl3)δ9.67(s，1H，-NH-1)，6.41(s，1H，-CONH-)，3.46(bs，2H，-CONHCH 2 CH2-)，2.93(t，2H，-CH2-4)，2.64～2.59(m，6H，-NHCH2 CH 2 N(CH 2 CH3)2)，2.58(s，3H，-CH3-2)，2.49(t，2H，-CH2-6)，2.16(m，2H，-CH2-5)，1.04(s，6H，-(CH2 CH 3 )2)；
ESI-MS：292.2[M+H]+，314.2[M+Na]+；290.3[M-H]-.
Example 3: n- (2-hydroxyethyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (II-2)
Using the method of example 2, 0.2g (1.0mmol) of 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (S4) and 0.13g (2.1mmol) of 2-aminoethanol were reacted, and the reaction solution was directly concentrated to give a solid which was purified by silica gel column chromatography (eluent dichloromethane: methanol 10: 1) to give 0.20g (85%) of the title compound as a white solid.
1HNMR(300MHz，DMSO-d6)δ11.84(s，1H，-NH-1)，7.17(t，1H，-CONH-)，4.69(t，1H，-OH)，3.48(q，2H，-CONHCH 2 CH2-)，3.28(q，2H，-CH 2 OH)，2.79(t，2H，-CH2-4)，2.34～2.31(m，5H，-CH3-2，-CH2-6)，1.97(m，2H，-CH2-5)；
ESI-MS：237.1[M+H]+，259.1[M+Na]+.
Example 4: n- (2-dimethylaminoethyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (II-3)
Figure A20061009820200212
Using the method of example 2, 0.2g (1.0mmol) 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (S4) and 0.19g (2.1mmol) N, N-dimethyl-1, 2-ethanediamine were reacted to give 0.21g (80%) of the title compound as a white solid.
1HNMR(300MHz，CDCl3)δ10.80(s，1H，-NH-1)，6.17(s，1H，-CONH-)，3.51(q，2H，-CONHCH 2 CH2-)，2.80(t，2H，-CH2-4)，2.55(t，2H，-CH2-6)，2.51(s，3H，-CH3-2)，2.46(t，2H，-CH 2 N(CH3)2)，2.29(s，6H，-CH2N(CH 3 )2)，2.09(m，2H，-CH2-5)；
ESI-MS：264.1[M+H]+，286.2[M+Na]+.
Example 5: n- (3-dimethylaminopropyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (II-4)
Figure A20061009820200213
Using the method of example 2, 0.2g (1.0mmol) 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (S4) and 0.21g (2.1mmol) N, N-dimethyl-1, 3-propanediamine reacted to give 0.23g (83%) of the title compound as a white solid.
1HNMR(300MHz，CDCl3)δ10.76(s，1H，-NH-1)，7.11(s，1H，-CONH-)，3.50(t，2H，-CONHCH 2 CH2CH2-)，2.89(t，2H，-CH2-4)，2.56(s，3H，-CH3-2)，2.50～2.41(m，4H，-CH2-6，-CH 2 N(CH3)2)，2.21(s，6H，-CH2N(CH 3 )2)，2.13(m，2H，-CH2-5)，1.72(m，2H，-CONHCH2 CH 2 CH2-)；
ESI-MS：278.2[M+H]+，300.1[M+Na]+.
Example 6: 2-methyl-7- [1, 2-dihydro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (IV-1)
Figure A20061009820200221
0.37g (2.8mmol) of 2-hydroxyindole and 0.5g (2.6mmol) of 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (S4) are dissolved in 15ml of anhydrous pyridine, TiCl is added40.4ml, stirring and reacting for 10 hours at 100-110 ℃, pouring into ice water, precipitating a large amount of solid, and reacting by using 6molAdjusting the pH value to 1-2 with/L hydrochloric acid, filtering, washing with water, and drying in vacuum to obtain 0.58g (72%) of a crude title compound as a tan solid, and recrystallizing with DMF and water to obtain 0.43g (54%) of the title compound as a yellow solid.
1HNMR(300MHz，DMSO-d6)δ14.64(s，1H，-NH-1)，12.03(s，1H，-COOH)，10.91(s，1H，-NH-1’)，7.63(d，1H，J＝7.56Hz，H-4’)，7.14(t，1H，H-6’)，6.99(t，1H，H-5’)，6.91(d，1H，J＝6.69Hz，H-7’)，3.12(t，2H，-CH2-4)，2.92(t，2H，-CH2-6)，2.53(s，3H，-CH3-2)，1.94(m，2H，-CH2-5)；
ESI-MS：307.2[M-H]-.
Example 7: 2-methyl-7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (IV-2)
Figure A20061009820200222
Using the method of example 6, the reaction temperature was adjusted to 50 ℃ to 60 ℃ and the reaction was carried out for 20 hours, and 0.42g (2.8mmol) of 5-fluoro-2-hydroxyindole was reacted with 0.5g (2.6mmol) of 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (S4) to give 0.30g (35%) of the title compound as a yellow solid.
1HNMR(300MHz，DMSO-d6)δ14.68(s，1H，-NH-1)，12.08(s，1H，-COOH)，10.93(s，1H，-NH-1’)，7.45(dd，1H，J＝11.91Hz，H-4’)，6.97(t，1H，H-6’)，6.87(t，1H，H-7’)，3.08(t，2H，-CH2-4)，2.92(t，2H，-CH2-6)，2.54(s，3H，-CH3-2)，1.94(m，2H，-CH2-5)；
ESI-MS：325.2[M-H]-.
Example 8: 2-methyl-7- [1, 2-dihydro-5-chloro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (IV-3)
Using the method of example 6, the reaction temperature was adjusted to 145 ℃ to 150 ℃ and the reaction time was 1 hour, 0.47g (2.8mmol) of 5-chloro-2-hydroxyindole was reacted with 0.5g (2.6mmol) of 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (S4) to give 0.28g (31%) of the title compound as a yellow solid.
1HNMR(500MHz，DMSO-d6)δ14.60(s，1H，-NH-1)，12.04(s，1H，-COOH)，11.04(s，1H，-NH-1’)，7.60(s，1H，H-4’)，7.42(d，1H，J＝8.5Hz，H-6’)，6.91(d，1H，J＝8.2Hz，H-7’)，3.08(t，2H，-CH2-4)，2.93(t，2H，-CH2-6)，2.54(s，3H，-CH3-2)，1.96(m，2H，-CH2-5)；
ESI-MS：341.1[M-H]-.
Example 9: 2-methyl-7- [1, 2-dihydro-5-methyl-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (IV-4)
Figure A20061009820200232
Using the method of example 6, the reaction temperature was adjusted to 80 ℃ to 90 ℃ and the reaction time was 13 hours, 0.41g (2.8mmol) of 5-methyl-2-hydroxyindole was reacted with 0.5g (2.6mmol) of 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (S4) to give 0.39g (46%) of the title compound as a yellow solid.
1HNMR(500MHz，DMSO-d6)δ14.66(s，1H，-NH-1)，12.03(s，1H，-COOH)，10.82(s，1H，-NH-1’)，7.46(s，1H，H-4’)，6.96(d，1H，J＝7.70Hz，H-6’)，6.80(d，1H，J＝7.75Hz，H-7’)，3.10(t，2H，-CH2-4)，2.93(t，2H，-CH2-6)，2.53(s，3H，-CH3-2)，2.32(s，3H，-CH3-5’)，1.95(m，2H，-CH2-5)；
ESI-MS：323.2[M+H]+；321.1[M-H]-.
Example 10: 2-methyl-7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid ethyl ester (I-1)
Figure A20061009820200233
Using the method of example 6, the reaction temperature was adjusted to 115 ℃ to 120 ℃ and the reaction time was 6 hours, after completion of the reaction between 0.39g (2.6mmol) of 5-fluoro-2-hydroxyindole and 0.5g (2.3mmol) of 2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid ethyl ester (S3), the reaction mixture was poured into ice water, extracted directly with dichloromethane, the organic layer was washed with water and a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and the resulting solid was concentrated and purified by silica gel column chromatography (eluent dichloromethane: ethyl acetate 4: 1) to obtain 0.22g (27%) of the title compound as a yellow solid.
1HNMR(500MHz，CDCl3)δ14.36(s，1H，-NH-1)，7.74(s，1H，-NH-1’)，7.36(d，1H，J＝10.53Hz，H-4’)，6.86～6.79(m，2H，H-6’，H-5’)，4.31(q，2H，-CH 2 CH3)，3.10(t，2H，-CH2-4)，3.05(t，2H，-CH2-6)，2.62(s，3H，-CH3-2)，2.05(m，2H，-CH2-5)，1.38(t，3H，-CH2 CH 3 ).
ESI-MS：355.3[M+H]+，377.2[M+Na]+；353.2[M-H]-.
Example 11: n- (2-diethylaminoethyl) -2-methyl-7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (I-2)
Figure A20061009820200241
0.12g (0.79mmol) of 5-fluoro-2-oxindole and 0.20g (0.69mmol) of N- (2-diethylaminoethyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (II-1) are dissolved in 10ml of anhydrous pyridine, TiCl is added4After 0.2ml of the reaction mixture was stirred at 100 ℃ to 110 ℃ for 10 hours, the reaction mixture was poured into ice water, extracted with dichloromethane, the organic layer was washed with water and a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and the resulting solid was concentrated and purified by silica gel column chromatography (eluent dichloromethane: methanol 30: 1) to obtain 0.09g (31%) of the title compound as a yellow solid.
1HNMR(300MHz，CDCl3)δ14.32(s，1H，-NH-1)，7.70(s，1H，-NH-1’)，7.36(dd，1H，J＝10.62Hz，H-4’)，6.91～6.78(m，2H，H-6’，H-7’)，6.44(bs，1H，-CONH-)，3.51(bs，2H，-CONHCH 2 CH2-)，3.11(t，2H，-CH2-4)，2.97(t，2H，-CH2-6)，2.62(bs，9H，-CH3-2，-NHCH2 CH 2 N(CH 2 CH3)2)，2.08(m，2H，-CH2-5)，1.07(bs，6H，-(CH2 CH 3 )2)；
ESI-MS：425.1[M+H]+.
Example 12: n- (2-diethylaminoethyl) -2-methyl-7- [1, 2-dihydro-5-chloro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (I-3)
Using the method of example 11, 0.13g (0.78mmol) of 5-chloro-2-hydroxyindole and 0.20g (0.69mmol) of N- (2-diethylaminoethyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (II-1) gave 0.08g (26%) of the title compound as a yellow solid.
1HNMR(500MHz，CDCl3)δ14.25(s，1H，-NH-1)，8.55(s，1H，-NH-1’)，7.55(s，1H，H-4’)，7.10(dd，1H，J＝8.2Hz，H-6’)，6.81(d，1H，J＝8.2Hz，H-7’)，6.48(s，1H，-CONH-)，3.51(s，2H，-CONHCH 2 CH2-)，3.06(t，2H，-CH2-4)，2.89(t，2H，-CH2-6)，2.68(s，2H，-CONHCH2 CH 2 -)，2.60(m，7H，-CH3-2，-NHCH2CH2N(CH 2 CH3)2)，2.03(m，2H，-CH2-5)，1.05(t，6H，-(CH2 CH 3 )2)；
ESI-MS：441.1[M+H]+，463.3[M+Na]+；439.2[M-H]-.
Example 13: n- (2-diethylaminoethyl) -2-methyl-7- [1, 2-dihydro-5-methyl-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (I-4)
Figure A20061009820200251
Using the method of example 11, 0.12g (0.82mmol) of 5-methyl-2-hydroxyindole and 0.20g (0.69mmol) of N- (2-diethylaminoethyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (II-1) reacted to give 0.09g (31%) of the title compound as a yellow solid.
1HNMR(300MHz，CDCl3)δ14.30(s，1H，-NH-1)，8.11(s，1H，-NH-1’)，7.42(s，1H，H-4’)，6.97(d，1H，J＝7.92Hz，H-6’)，6.80(d，1H，J＝7.83Hz，H-7’)，6.47(bs，1H，-CONH-)，3.51(m，2H，-CONHCH 2 CH2-)，3.14(t，2H，-CH2-4)，2.94(t，2H，-CH2-6)，2.68～2.57(m，9H，-CH3-2，-NHCH2 CH 2 N(CH 2 CH3)2)，2.38(s，3H，-CH3-5’)，2.03(m，2H，-CH2-5)，1.05(t，6H，-(CH2 CH 3 )2)；
ESI-MS：421.1[M+H]+.
Example 14: n- (2-diethylaminoethyl) -2-methyl-7- [1, 2-dihydro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indol-3-carboxamide (I-5)
Figure A20061009820200252
Using the method of example 11, 0.11g (0.83mmol) 2-hydroxyindole and 0.20g (0.69mmol) N- (2-diethylaminoethyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (II-1) reacted to give 0.09g (32%) of the title compound as a yellow solid.
1HNMR(300MHz，CDCl3)δ14.27(s，1H，-NH-1)，8.06(s，1H，-NH-1’)，7.62(s，1H，J＝7.71Hz，H-4’)，7.15(t，1H，H-6’)，7.04(t，1H，H-5’)，6.91(d，1H，J＝7.56Hz，H-7’)，6.46(bs，1H，-CONH-)，3.51(m，2H，-CONHCH 2 CH2-)，3.15(t，2H，-CH2-4)，2.93(t，2H，-CH2-6)，2.67～2.59(m，9H，-CH3-2，-NHCH2 CH 2 N(CH 2 CH3)2)，2.05(m，2H，-CH2-5)，1.05(t，6H，-(CH2 CH 3 )2)；
ESI-MS：407.3[M+H]+.
Example 15: n- (2-dimethylaminoethyl) -2-methyl-7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (I-6)
Figure A20061009820200253
Using the method of example 11, 0.13g (0.86mmol) of 5-fluoro-2-oxindole and 0.18g (0.68mmol) of N- (2-dimethylaminoethyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (II-3) reacted to give 0.09g (33%) of the title compound as a yellow solid.
1HNMR(300MHz，CDCl3)δ14.21(s，1H，-NH-1)，8.70(s，1H，-NH-1’)，7.32(d，1H，J＝12.07Hz，H-4’)，6.87～6.76(m，2H，H-6’，H-7’)，6.59(bs，1H，-CONH-)，3.57(m，2H，-CONHCH 2 CH2-)，2.99(t，2H，-CH2-4)，2.76(t，2H，-CH2-6)，2.65(s，2H，-NHCH2 CH 2 N(CH3)2)，2.57(s，3H，-CH3-2)，2.38(s，6H，-N(CH 3 )2)，1.94(m，2H，-CH2-5)；
ESI-MS：397.3[M+H]+.
Example 16: n- (3-dimethylaminopropyl) -2-methyl-7- [1, 2-dihydro-5-chloro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (I-7)
Using the method of example 11, 0.13g (0.78mmol) of 5-chloro-2-hydroxyindole and 0.20g (0.72mmol) of N- (3-dimethylaminopropyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (II-4) reacted to give 0.10g (33%) of the title compound as a yellow solid.
1HNMR(300MHz，CDCl3)δ14.25(s，1H，-NH-1)，7.83(s，1H，-NH-1’)，7.59(s，1H，H-4’)，7.12(m，2H，H-6’，-CONH-)，6.83(d，1H，J＝8.28Hz，H-7’)，3.54(s，2H，-CONHCH 2 CH2CH2-)，3.11(s，2H，-CH2-4)，2.94(s，2H，-CH2-6)，2.60(s，3H，-CH3-2)，2.51(s，2H，-CONHCH2CH2 CH 2 -)，2.28(s，6H，-N(CH 3 )2)，2.07(m，2H，-CH2-5)，1.79(bs，2H，-CONHCH2 CH 2 CH2-)；
ESI-MS：427.2[M+H]+.
Example 17: n- (2-hydroxyethyl) -2-methyl-7- [1, 2-dihydro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (I-8)
Using the method of example 11, 0.11g (0.83mmol) 2-hydroxyindole and 0.17g (0.72mmol) N- (2-hydroxyethyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (II-2) react to give 0.07g (28%) of the title compound as a yellow solid.
1HNMR(300MHz，CDCl3)δ14.49(s，1H，-NH-1)，10.83(s，1H，-NH-1’)，7.64(d，1H，J＝7.83Hz，H-4’)，7.26(t，1H，-CONH-)，7.13(t，1H，H-6’)，7.01～6.91(m，2H，H-5’，H-7’)，4.65(bs，1H，-OH)，3.51(s，2H，-CONHCH 2 CH2-)，3.31(m，2H，-CONHCH2 CH 2 -)，3.13(t，2H，-CH2-4)，2.84(t，2H，-CH2-6)，2.46(s，3H，-CH3-2)，1.99(m，2H，-CH2-5)；
ESI-MS：352.3[M+H]+，374.1[M+Na]+；350.2[M-H]-.
Example 18: n- (2-hydroxyethyl) -2-methyl-7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (I-9)
Figure A20061009820200271
Using the method of example 11, 0.13g (0.86mmol) of 5-fluoro-2-oxindole and 0.17g (0.72mmol) of N- (2-hydroxyethyl) -2-methyl-7-oxo-4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide (II-2) reacted to give 0.08g (30%) of the title compound as a yellow solid.
1HNMR(300MHz，CDCl3)δ14.54(s，1H，-NH-1)，10.84(s，1H，-NH-1’)，7.44(dd，1H，J＝10.9Hz，H-4’)，7.26(t，1H，-CONH-)，6.98～6.85(m，2H，H-6’，H-7’)，4.63(t，1H，-OH)，3.52(q，2H，-CONHCH 2 CH2-)，3.32(m，2H，-CONHCH2 CH 2 -)，3.08(t，2H，-CH2-4)，2.85(t，2H，-CH2-6)，2.47(s，3H，-CH3-2)，1.98(m，2H，-CH2-5)；
ESI-MS：368.1[M-H]-.
Example 19: 2-methyl-3- (morpholine-4-carbonyl) -7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indol (I-10)
Figure A20061009820200272
Using the procedure of example 2, 0.15g (0.46mmol) 2-methyl-7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (IV-2) and 0.13g (1.5mmol) morpholine were reacted to give 0.12g (66%) of the title compound as a yellow solid.
1HNMR(300MHz，CDCl3)δ14.23(s，1H，-NH-1)，7.95(s，1H，-NH-1’)，7.35(dd，1H，J＝10.58Hz，H-4’)，6.88～6.77(m，2H，H-6’，H-7’)，3.69(s，4H，-N(CH 2 CH2)2O)，3.63(s，4H，-N(CH2 CH 2 )2O)，3.09(t，2H，-CH2-4)，2.70(t，2H，-CH2-6)，2.42(s，3H，-CH3-2)，2.06(m，2H，-CH2-5)；
ESI-MS：396.2[M+H]+，418.2[M+Na]+，434.0[M+K]+；394.2[M-H]-.
Example 20: 2-methyl-3- (morpholine-4-carbonyl) -7- [1, 2-dihydro-5-chloro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indol (I-11)
Using the procedure of example 2, 0.15g (0.44mmol) 2-methyl-7- [1, 2-dihydro-5-chloro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (IV-3) and 0.12g (1.4mmol) morpholine were reacted to give 0.13g (72%) of the title compound as a yellow solid.
1HNMR(500MHz，CDCl3)δ14.19(s，1H，-NH-1)，7.90(s，1H，-NH-1’)，7.59(s，1H，H-4’)，7.12(dd，1H，J＝8.19Hz，H-6’)，6.82(d，1H，J＝8.23Hz，H-7’)，3.70(s，4H，-N(CH 2 CH2)2O)，3.63(s，4H，-N(CH2 CH 2 ) 2 O)，3.12(s，2H，-CH2-4)，2.71(s，2H，-CH2-6)，2.43(s，3H，-CH3-2)，2.06(m，2H，-CH2-5)；
ESI-MS：412.2[M+H]+，434.1[M+Na]+；410.2[M-H]-.
Example 21: 2-methyl-3- (morpholine-4-carbonyl) -7- [1, 2-dihydro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indol (I-12)
Figure A20061009820200282
Using the method of example 2, 0.14g (0.45mmol) 2-methyl-7- [1, 2-dihydro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (IV-1) and 0.13g (1.5mmol) morpholine gave 0.12g (71%) of the title compound as a yellow solid.
1HNMR(300MHz，CDCl3)δ14.20(s，1H，-NH-1)，8.07(s，1H，-NH-1’)，7.63(d，1H，J＝7.86Hz，H-4’)，7.16(t，1H，H-6’)，7.05(t，1H，H-5’)，6.90(dd，1H，J＝7.63Hz，H-7’)，3.70(s，4H，-N(CH 2 CH2)2O)，3.64(s，4H，-N(CH2 CH 2 )2O)，3.15(t，2H，-CH2-4)，2.70(s，2H，-CH2-6)，2.42(s，3H，-CH3-2)，2.05(m，2H，-CH2-5)；
ESI-MS：378.1[M+H]+；376.2[M-H]-.
Example 22: 2-methyl-3- (4-methyl-piperazine-1-carbonyl) -7- [1, 2-dihydro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole (I-13)
Using the method of example 2, 0.15g (0.49mmol) 2-methyl-7- [1, 2-dihydro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (IV-1) and 0.15g (1.5mmol) N-methylpiperazine were reacted to give 0.14g (73%) of the title compound as a yellow solid.
1HNMR(300MHz，CDCl3)δ14.17(s，1H，-NH-1)，7.90(s，1H，-NH-1’)，7.64(d，1H，J＝7.83Hz，H-4’)，7.15(t，1H，H-6’)，7.05(t，1H，H-5’)，6.91(d，1H，J＝7.60Hz，H-7’)，3.65(s，4H，-N(CH 2 CH2)2NCH3)，3.16(t，2H，-CH2-4)，2.70(s，2H，-CH2-6)，2.41(s，7H，-CH3-2，-N(CH2 CH 2 )2NCH3)，2.33(s，3H，-N(CH2CH2)2NCH 3 )，2.06(m，2H，-CH2-5)；
ESI-MS：391.2[M+H]+；389.2[M-H]-.
Example 23: 2-methyl-3- (4-methyl-piperazine-1-carbonyl) -7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole (I-14)
Figure A20061009820200291
Using the procedure of example 2, 0.15g (0.46mmol) 2-methyl-7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (IV-2) and 0.15g (1.5mmol) N-methylpiperazine were reacted to give 0.14g (75%) of the title compound as a yellow solid.
1HNMR(300MHz，CDCl3)δ14.21(s，1H，-NH-1)，7.70(s，1H，-NH-1’)，7.36(dd，1H，J＝10.61Hz，H-4’)，6.89～6.78(m，2H，H-6’，H-7’)，3.66(bs，4H，-N(CH 2 CH2)2NCH3)，3.11(t，2H，-CH2-4)，2.71(s，2H，-CH2-6)，2.42(s，7H，-CH3-2，-N(CH2 CH 2 )2NCH3)，2.35(s，3H，-N(CH2CH2)2NCH 3 )，2.06(m，2H，-CH2-5)；
ESI-MS：409.3[M+H]+；407.3[M-H]-.
Example 24: n, N-dimethyl-2-methyl-7- [1, 2-dihydro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indol-3-carboxamide (I-15)
Figure A20061009820200292
Using the method of example 2, 0.10g (0.32mmol) 2-methyl-7- [1, 2-dihydro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid (IV-1) and 0.12g (1.5mmol) dimethylamine hydrochloride and adding 0.23g (1.5mmol) DBU, reaction gave 50mg (47%) of the title compound as a yellow solid.
1HNMR(500MHz，CDCl3)δ14.14(s，1H，-NH-1)，7.85(bs，1H，-NH-1’)，7.63(s，1H，J＝7.90Hz，H-4’)，7.15(t，1H，H-6’)，7.04(t，1H，H-5’)，6.90(d，1H，J＝7.64Hz，H-7’)，3.16(s，2H，-CH2-4)，3.06(s，3H，-NCH 3 (CH3))，2.71(s，2H，-CH2-6)，2.40(s，3H，-CH3-2)，2.04(m，2H，-CH2-5)，1.57(s，3H，-NCH3(CH 3 ))；
ESI-MS：336.1[M+H]+；334.2[M-H]-.
Biological examples
Those compounds having the best degree of desired activity were screened using the following assay.
Method for measuring tumor cell proliferation inhibition (MTT method)
The measurement is carried out by the conventional tetrazolium bromide (MTT) method. Succinate dehydrogenase in mitochondria of living cells can reduce exogenous tetrazolium bromide into insoluble bluish purple crystals (Formazan) and deposit in cells, while dead cells do not have the function. Dimethyl sulfoxide (DMSO) can dissolve purple crystals in cells, and an enzyme linked immunosorbent assay (ELISA) detector is used for measuring the light absorption value at the wavelength of 570nm, so that the quantity of living cells can be indirectly reflected. Thus, the ability of the compounds of the present invention to inhibit cell proliferation can be determined using the MTT method, while similar assays can be used on any cancer cell using methods well known in the art.
1. Reagent and apparatus
RPMI1640 medium (RPMI 1640+ 12% calf serum + HEPES 3.5g/l + NaHCO)32.2g/l + penicillin 0.13g/l + streptomycin 0.15 g/l);
RPMI1640 medium (RPMI 1640+ 12% fetal bovine serum + HEPES 3.5g/l + NaHCO)32.2g/l + penicillin 0.13g/l + streptomycin 0.15 g/l);
high-sugar DMEM medium (DMEM + 10% calf serum + HEPES 3.5g/l + NaHCO)32.2g/l + penicillin 0.13g/l + streptomycin 0.15 g/l);
high-glucose DMEM medium (DMEM + 12% fetal bovine serum + HEPES 3.5g/l + NaHCO)32.2g/l + penicillin 0.13g/l + streptomycin 0.15 g/l);
MC COYS 5-A medium (DMEM + 12% fetal bovine serum + HEPES 3.5g/l + NaHCO)32.2g/l + penicillin 0.13g/l + streptomycin 0.15 g/l);
(ii) trypsin;
MTT (product of Amresco, USA);
test compounds: compounds I-1 to I-15 prepared in the examples of the present invention;
enzyme mark instrument (TECAN infinite M200)
2. Cancer cell line
2.1 human gastric adenocarcinoma cell line (BGC)
2.2 human non-small cell lung cancer (A549)
2.3 human leukemia cell line (K562)
2.4 human pancreatic cancer cell line (PANC-1)
2.5 human Small cell Lung cancer (NCI-H446)
Cancer cell lines listed as 2.1, 2.2, 2.3, 2.4 and 2.5 were cultured in RPMI1640 medium containing 12% calf serum at 37 deg.C under 5% CO2Culturing in an incubator;
2.6 human pancreatic cancer cell line (BXPC-3)
2.7 human bladder cancer cell line (T24)
Cancer cell lines as listed in 2.6 and 2.7 were cultured in 12% fetal bovine serum RPMI1640 medium at 37 ℃ in 5% CO2Culturing in an incubator;
2.8 human hepatoma cell line (HEPG2)
2.9 human Breast cancer cell line (MCF-7)
As in 2.8 and 2.9Cancer cell line with high-sugar DMEM medium containing 12% calf serum at 37 deg.C and 5% CO2Culturing in an incubator;
2.10 human colon adenocarcinoma cell line (CACO-2)
Cancer cell lines listed as 2.10 were cultured in 12% fetal bovine serum in high-glucose DMEM at 37 deg.C and 5% CO2Culturing in an incubator;
2.11 human colon cancer cell line (HT29)
2.12 human Colon cancer cell line (HCT116)
2.13 human ovarian cancer cell line (SK-OV-3)
Cancer cell lines as listed in 2.11, 2.12 and 2.13 were cultured in MC COYS 5-A medium of 12% fetal bovine serum at 37 ℃ in 5% CO2Cultured in an incubator.
3. Experimental methods
3.1 inoculation: taking a bottle of cells in exponential growth phase with good state, adding appropriate amount of trypsin digestive fluid, digesting to make adherent cells shed, preparing cell suspension with RPMI1640 (or DMEM or 5A) culture solution containing 12% calf serum, counting, and adjusting and diluting cell density to 1.67 × 104Cell suspension was taken out at a concentration of 180 ul/well (3000 tumor cells/well) and seeded on a 96-well plate.
3.2 culturing: transfer the plates to constant temperature CO2In an incubator at 37 ℃ with 5% CO2And culturing under saturated humidity condition for 24 hours.
3.3 primary screening: the test compound is first prepared with DMSO to 0.1M concentration and then diluted 3 times for preliminary screening, with the concentration of 10-5mol/L、10-6mol/L and 10-7mol/L. Test compounds were added at 20 ul/well and incubated for 72 hours. Each group is provided with 3 parallel holes and repeated for 3 times, the light absorption value of each hole of a 96-hole plate is measured, the result is recorded, the cell growth inhibition rate is calculated, and the average value of three times is taken.
3.4 dyeing:
3.4.1 MTT was added to 96-well plates (adherent cells) at 20 ul/well and incubated in an incubator for 4 hours, the supernatant in the wells was aspirated, DMSO at 100 ul/well was added and shaken on a plate shaker for 5 minutes.
3.4.2 MTT was added to a 96-well plate (cell suspension), 20 ul/well, incubated in an incubator for 4 hours, followed by 20% SDS 50 ul/well and placed in the incubator overnight.
3.5 determination: setting the wavelength of the microplate reader to 570nm and the reference wavelength to 630nm, measuring the light absorption value of each hole of a 96-hole plate, recording the result and calculating the cell growth inhibition rate so as to judge the anti-tumor activity of the tested medicine.
3.6 re-screening: at a preliminary screening concentration of 10-5When mol/L, the compound with the cell inhibition rate more than or equal to 50 percent for 3 times is used for re-screening, 0.1mol/L is diluted by 10 times, and the concentration is 10 in sequence-5mol/L、0.5×10-5mol/L、10-6mol/L、0.8×10-6mol/L、0.6×10-6mol/L、0.4×10-6mol/L、0.2×10-6mol/L、10-7mol/L、0.8×10-7mol/L and 0.4X 10-7mol/L. Test compounds were added at 20 ul/well and incubated for 48 hours. Likewise, 3 parallel wells per group were set and repeated 3 times, and the absorbance of each well of the 96-well plate was measured according to the primary screening method, and the results were recorded and the cell growth inhibition rate was calculated.
3.7 inhibition of cell growth and IC50The calculation of (2):
Figure A20061009820200311
meanwhile, according to the growth inhibition rate of each concentration, the logarithm of the concentration of the compound is the same as the Logit [ I ]]Linear regression to determine the concentration of test compound, i.e., IC, at which the growth inhibition rate was 50%50And taking the average value of three times.
4. Results of the experiment
4.1 cell growth inhibition Rate
At a concentration of 10-5mol/L, the growth inhibition rate of the compound of the invention to different tumor cells is respectively shown in the following tables 1 and 2:
TABLE 1
TABLE 2
Figure A20061009820200331
4.2 half Inhibitory Concentration (IC) for cell growth50umol/L)
Half maximal Inhibitory Concentration (IC) of the compounds of the invention on the growth of different tumor cells50) See tables 3 and 4, respectively:
TABLE 3
Figure A20061009820200332
TABLE 4
Figure A20061009820200333
5. Conclusion of the experiment
Prepared in the examples of the inventionThe compounds I-1 to I-15 with the structure of the formula (I) have inhibition effect on the proliferation of various tumor cells, wherein the inhibition effect of the compounds I-2 to I-8 on the proliferation of the tumor cells is more obvious, and the IC of the compounds is50At 10-5mol/L is less than. The compounds can be applied to the preparation of antitumor drugs.

Claims (18)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure A2006100982020002C1
wherein,
R1is hydrogen, halogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, -C (O) R7、-NR8R9、-(CH2)nR10or-C(O)NR11R12；
R2Is hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy, cyano, -NR8R9、-NR8C(O)R9、-C(O)R7Aryl, heteroaryl, -S (O)2NR8R9or-SO2R13；
R3Is hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy, -C (O) R7、-NR8R9Aryl, heteroaryl, -NR8S(O)2R9、-S(O)2NR8R9、-NR8C(O)R9、-NR8C(O)OR9or-SO2R13；
R4Is hydrogen, halogen, alkyl, hydroxy, alkoxy or-NR8R9；
R5Is hydrogen, alkyl or-C (O) R14；
R6Is hydroxy, alkoxy, aryloxy, -N (R)15)(CH2)rR16or-NR8R9；
R7Is hydrogen, hydroxy, alkoxy or aryloxy;
R10is hydroxy, -C (O) R7、-NR8R9or-C (O) NR8R9；
R11And R12Independently selected from hydrogen, alkyl or aryl, or R11And R12Together with the nitrogen atom to which they are attached form a heterocyclic group;
R13is alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
R14is hydroxy, alkoxy, aryloxy or-NR8R9；
R15Is hydrogen or alkyl;
R15is hydroxy, -NR8R9、-C(O)R7Aryl, heteroaryl, -N+(O-)R8R9、-N(OH)R8or-NHC (O) RaWhereinRaIs unsubstituted alkyl, haloalkyl or aralkyl;
R8and R9Independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R8And R9Taken together to form a heterocyclic group;
n and r are independently 1, 2, 3 or 4.
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
R1、R3And R4Is hydrogen;
R2is hydrogen, halogen or alkyl;
R5is methyl;
R6is hydroxy or-NR8R9；
R8And R9Independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R8And R9Taken together to form a heterocyclic group;
r is 2 or 3.
3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
2-methyl-7- [1, 2-dihydro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid;
2-methyl-7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid;
2-methyl-7- [1, 2-dihydro-5-chloro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid;
2-methyl-7- [1, 2-dihydro-5-methyl-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid;
2-methyl-7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxylic acid ethyl ester;
n, N-dimethyl-2-methyl-7- [1, 2-dihydro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide;
2-methyl-3- (morpholine-4-carbonyl) -7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole;
2-methyl-3- (morpholine-4-carbonyl) -7- [1, 2-dihydro-5-chloro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole;
2-methyl-3- (morpholine-4-carbonyl) -7- [1, 2-dihydro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole;
2-methyl-3- (4-methyl-piperazine-1-carbonyl) -7- [1, 2-dihydro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole;
2-methyl-3- (4-methyl-piperazine-1-carbonyl) -7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole.
4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
R1、R3And R4Is hydrogen;
R2is hydrogen, halogen or alkyl;
R5is methyl;
R6is-N (R)15)(CH2)rR16；
R15Is hydrogen;
R16is hydroxy or-NR8R9；
R8And R9Independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R8And R9Taken together to form a heterocyclic group;
r is 2 or 3.
5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
2-methyl-7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide;
2-methyl-7- [1, 2-dihydro-5-chloro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide;
n- (2-diethylaminoethyl) -2-methyl-7- [1, 2-dihydro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide;
n- (2-diethylaminoethyl) -2-methyl-7- [1, 2-dihydro-5-methyl-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide;
2-methyl-7- [1, 2-dihydro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide;
2-methyl-7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide;
2-methyl-7- [1, 2-dihydro-5-fluoro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide;
n- (3-dimethylaminopropyl) -2-methyl-7- [1, 2-dihydro-5-chloro-2-oxo-3H-indol- (Z) -3-ylidene ] -4, 5, 6, 7-tetrahydro-1H-indole-3-carboxamide.
6. A process for the preparation of a compound of formula (I), characterized in that a compound of formula (III) is reacted with a compound of formula (II) in an aprotic solvent in the presence of a Lewis acid at a temperature of from 50 ℃ to 150 ℃ for a time of from 1 hour to 20 hours, according to the following reaction equation:
wherein R is1、R2、R3、R4、R5、R6Is as defined in claim 1.
7. The method of claim 6, wherein the Lewis acid is AlCl3、BF3、SnCl4、SnCl2、ZnCl2Or TiCl4。
8. Preparation process according to claim 7, characterized in that the Lewis acid is SnCl4Or TiCl4。
9. The process according to claim 8, wherein the Lewis acid is TiCl4。
10. The method according to claim 6, wherein the aprotic solvent is selected from the group consisting of aprotic solvents such as N, N-dimethylformamide, acetone, acetonitrile, dimethylsulfoxide, and pyridine, and inert solvents such as pentane, hexane, cyclohexane, benzene, and toluene.
11. The process according to claim 10, wherein the aprotic solvent is pyridine.
12. The method according to claim 6, wherein the reaction temperature is 85 to 120 ℃.
13. The method according to claim 12, wherein the reaction temperature is 100 ℃ to 110 ℃.
14. The method according to claim 6, wherein the reaction time is 5 to 13 hours.
15. The method according to claim 14, wherein the reaction time is 8 to 10 hours.
16. Use of a compound according to any one of claims 1 to 5 for the preparation of an anti-neoplastic medicament.
17. An intermediate of formula (II):
Figure A2006100982020005C1
wherein:
R5is hydrogen, alkyl or-C (O) R14；
R6Is hydroxy, alkoxy, aryloxy, -N (R)15)(CH2)rR16or-NR8R9；
R15Is hydrogen or alkyl;
R16is hydroxy, -NR8R9、-C(O)R7Aryl, heteroaryl, -N+(O-)R8R9、-N(OH)R8or-NHC (O) RaWherein R isaIs unsubstituted alkyl, haloalkyl or aralkyl; r7Is hydrogen, hydroxy, alkoxy or aryloxy;
R8and R9Independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R8And R9Taken together to form a heterocyclic group;
r is 1, 2, 3 or 4.
18. The intermediate of claim 17, wherein
R5Is methyl;
R6is hydroxy, ethoxy or-N (R)15)(CH2)rR16；
R15Is hydrogen or alkyl;
R16is hydroxy or-NR8R9；
R8And R9Independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R8And R9Taken togetherForming a heterocyclic group;
r is 2 or 3.
CNA200610098202XA 2006-12-04 2006-12-04 2-dihydro indolone derivant, preparation method and application thereof Pending CN101195601A (en)

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CN102532118A (en) * 2010-12-24 2012-07-04 沈阳药科大学 Indolone-containing 4-thiazolidone derivatives and application thereof
CN102675183A (en) * 2011-03-11 2012-09-19 江苏先声药物研究有限公司 Method for preparing medical intermediate on large scale
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102532118A (en) * 2010-12-24 2012-07-04 沈阳药科大学 Indolone-containing 4-thiazolidone derivatives and application thereof
CN102532118B (en) * 2010-12-24 2014-04-09 沈阳药科大学 Indolone-containing 4-thiazolidone derivatives and application thereof
CN102675183A (en) * 2011-03-11 2012-09-19 江苏先声药物研究有限公司 Method for preparing medical intermediate on large scale
CN102675183B (en) * 2011-03-11 2014-07-16 南京优科生物医药研究有限公司 Method for preparing medical intermediate on large scale
WO2012122921A1 (en) * 2011-03-15 2012-09-20 江苏先声药物研究有限公司 Salt form of hydroxyphenylalanine kinase inhibitor
CN103298784A (en) * 2011-03-15 2013-09-11 江苏先声药物研究有限公司 Salt form of hydroxyphenylalanine kinase inhibitor
CN103298784B (en) * 2011-03-15 2015-07-15 南京优科生物医药研究有限公司 Salt form of hydroxyphenylalanine kinase inhibitor
CN103664738A (en) * 2012-09-12 2014-03-26 南京优科生物医药研究有限公司 Crystalline polymorphic substance of carboxamide compound L-malate
CN104876851A (en) * 2015-05-15 2015-09-02 南京大学 Preparation method of piperazidine derivatives containing indolyl-3-carboxylic acid skeleton and application of piperazidine derivatives in anticancer drugs
CN114213396A (en) * 2022-01-27 2022-03-22 深圳市乐土生物医药有限公司 Indole-2-ketone compound and preparation method and application thereof

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