KR101800876B1 - Novel Diarylisoquinolines and Pharmaceutical Composition Comprising the Same - Google Patents
Novel Diarylisoquinolines and Pharmaceutical Composition Comprising the Same Download PDFInfo
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- KR101800876B1 KR101800876B1 KR1020150150055A KR20150150055A KR101800876B1 KR 101800876 B1 KR101800876 B1 KR 101800876B1 KR 1020150150055 A KR1020150150055 A KR 1020150150055A KR 20150150055 A KR20150150055 A KR 20150150055A KR 101800876 B1 KR101800876 B1 KR 101800876B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
Abstract
The present invention relates to novel diarylisoquinolones or diarylisoquinolines compounds. The compounds of the present invention exhibit selective cytotoxicity in human cancer cells (T47D), human prostate cancer cell line (DU145) and human rectal adenocarcinoma cell line (HCT-15), which are cancer cells, and in particular CPT and etoposide (etoposide). < / RTI > Also, 3,4-diarylisoquinolone in the compounds of the present invention exhibits an inhibitory activity against topo II, 3,4-diarylisoquinoline amine exhibits excellent topo I inhibitory activity, and diaryl-substituted Isoquinoline can be used as an anticancer agent.
Description
The present invention relates to a novel diarylisoquinolone or diarylisoquinoline compound and a pharmaceutical composition containing the same.
Topoisomerases (topos) are essential enzymes for cell growth and proliferation. This enzyme is involved in topological changes in DMA, such as DNA supercoils, knots, and catenation during cellular processes such as transcription, recombination, and replication [1]. Topos is overexpressed in cancer cells because it is involved in activities essential for cell growth and division [2-6]. Thus, topo inhibition is an important mechanism in the treatment of cancer.
The human genome codes for six types of topos, and topo I and II are therapeutically important. The US Food and Drug Administration administers various topo I and II drugs such as topotecan (camptothecin derivative), etoposide and doxorubicin (DOX) as treatments for ovarian cancer, small cell lung cancer, colon cancer and thyroid cancer as well as acute lymphoblastic leukemia and acute myelogenous white blood Inhibitor (see Figure 1). Although these topo inhibitors have anticancer activity, they have problems such as low instability of chemical instability, drug resistance by cells overexpressing drug-releasing membrane transporter, and secondary drug-related tumors [7, 8]. Clinically, the most common strategy to overcome the shortcomings of prescription drugs is to remove functional groups with chemical reactivity, add functional groups (amine groups) to increase solubility, or use chemical species with new scaffolds Thereby reducing the reactivity of the emissive film transporter to the substrate. In view of these facts, the present inventors have invented a 3-arylisoquinoline derivative which can replace the topo inhibitor (see FIG. 2).
Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.
The present inventors sought to develop a more potent and specific anticancer agent having topo isomerase (topo) inhibitory activity. As a result, the present inventors have found that the use of a diarylisoquinoline series compound (3,4-diarylisoquinoline and 3-diarylisoquinoline) using a lithium talloamide-benzonitrile addition cycloaddition, Suzuki coupling and a nucleophilic aromatic substitution reaction , 4-diarylisoquinoline amine) were synthesized. The eight derivatives of the compounds do not show toxicity in the noncancerous human mammary epithelial cell line (MCF10A), whereas the eight derivatives of the compounds show no toxicity in the noncancerous human mammary epithelial cell line (MCF10A), while the human carcinoma epithelial cancer cell line (T47D), human prostate cancer cell line (DU145) -15). In particular, it was confirmed that the compound exhibited an excellent inhibitory effect as compared with the conventional topo inhibitors CPT and etoposide, thereby completing the present invention.
Accordingly, an object of the present invention is to provide a novel diarylisoquinolone compound.
Another object of the present invention is to provide a novel diarylisoquinoline compound.
Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer comprising the diarylisoquinoline or diarylisoquinoline compound of the present invention.
Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
According to one aspect of the present invention, there is provided a diarylisoquinolone compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
In
According to another aspect of the present invention, there is provided a diarylisoquinoline compound represented by the following formula (2): < EMI ID =
(2)
In
The present inventors have made intensive studies to develop a more potent and specific anticancer agent having topo isomerase (topo) inhibitory activity. As a result, it has been found that the lithium tallamide-benzonitrile addition cycloaddition, Suzuki coupling, Diarylisoquinoline series compounds (3,4-diarylisoquinoline and 3,4-diarylisoquinoline amine) were synthesized by the reaction. The eight derivatives of the compounds do not show toxicity in the noncancerous human mammary epithelial cell line (MCF10A), whereas the eight derivatives of the compounds show no toxicity in the noncancerous human mammary epithelial cell line (MCF10A), while the human carcinoma epithelial cancer cell line (T47D), human prostate cancer cell line (DU145) -15). Especially, the inhibitory effect was superior to that of CPT and etoposide, which are topo inhibitors.
The present inventors have found that, as a cytotoxic drug having topo inhibitory activity with physicochemical pharmacokinetic properties suitable for oral administration in the prior art [13,14], 3-arylisoquinolone 1 [9], 3-arylisoquinoline amine 2 [ Amino-2-phenylquinazoline 3 [11] and 3-heteroarylisoquinolinamine 4 [12] were synthesized and the structure-activity relationship (SAR) of 3-arylisoquinoline was investigated. In the study, their cytotoxicity and topo inhibitory activity were found to be compound structure dependent. Considering that subtle changes in structure may lead to significant changes in pharmacological activity, the present inventors designed 3,4-
As used herein, the term " alkyl " used to define the diarylisoquinolone of formula (1) and the diarylisoquinoline of formula (2) means a straight or branched unsubstituted or substituted saturated hydrocarbon group, , Ethyl, propyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, tridecyl, pentadecyl and heptadecyl and the like. C 1 -3 alkyl having a carbon number in the case where means an alkyl group that has an alkyl unit having 1-3 carbon atoms, and the C 1-3 alkyl substituted with a substituent is not included. In the formulas (1) and (2), C 1-3 alkyl is preferably C 1-2 alkyl.
The term " alkoxy " refers to an -O alkyl group, including, for example, ethoxy, methoxy and the like, where the C 1-3 alkoxy is substituted, the carbon number of the substituent is not included.
The term " aryl " means a fully or partially unsaturated substituted or unsubstituted monocyclic or polycyclic carbon ring. C 6 -10 aryl group is not included in the carbon number of the substituent when the aryl group means a group having a carbon ring atom of a carbon number of 6 to 10, C 6-10 aryl is optionally substituted. Preferably the aryl is monoaryl or biaryl. The monoaryl preferably has from 5 to 6 carbon atoms, and the biaryl preferably has from 9 to 10 carbon atoms. Preferably, said aryl is substituted or unsubstituted phenyl. When monoaryl, for example phenyl, is substituted, substitution can be made at various positions by various substituents, including halo, hydroxy, nitro, cyano, C 1 -C 4 substituted or unsubstituted straight or branched Chain alkyl or C 1 -C 4 straight chain or branched chain alkoxy.
The term " arylalkyl ", on the other hand, consists of a fully or partially unsaturated substituted or unsubstituted monocyclic or polycyclic carbon ring and an alkyl group. C 6 -10 aryl is meant an aryl group having carbon atoms of 6 to 10 carbon atoms, having a carbon number in the case where the C 6-10 aryl substituted alkyl substituent is not included. When arylalkyl is substituted, it can be substituted by various substituents at various positions, and includes, for example, halo, hydroxy, nitro, cyano, C 1 -C 4 substituted or unsubstituted straight or branched chain alkyl or C Lt; / RTI > may be substituted by 1 to 4 straight-chain or branched alkoxy.
&Quot; Arylalkoxy " refers to a fully or partially unsaturated substituted or unsubstituted monocyclic or polycyclic carbon ring and alkoxy. C 6 -10 aryl means a aryl-alkoxy having a carbon atom of a carbon number of 6 to 10, C 6-10 aryl alkoksiyi carbon atoms when substituted the substituent is not included. When arylalkoxy is substituted, it can be substituted by various substituents at various positions, and includes, for example, halo, hydroxy, nitro, cyano, C 1 -C 4 substituted or unsubstituted straight or branched chain alkyl or C Lt; / RTI > may be substituted by 1 to 4 straight-chain or branched alkoxy. According to a particular embodiment of the invention, said arylalkoxy is benzylalkoxy, more preferably benzylmethoxy.
The term " heterocycloalkyl containing oxygen, sulfur or nitrogen as heteroatom " means a non-aromatic cyclic hydrocarbon group containing carbon and hydrogen and at least one heteroatom (oxygen, sulfur or nitrogen). The heteroatom is preferably oxygen or nitrogen, and most preferably nitrogen. The number of heteroatoms may be 1-4, 1-3, 1-2, or 1. C 4 -5 heterocycloalkyl means heterocycloalkyl in which the number of carbons forming the ring structure is 4-5. When heterocycloalkyl is substituted, substitution can be made by various substituents at various positions, including, for example, halo, hydroxy, nitro, cyano, C 1 -C 4 substituted or unsubstituted straight or branched chain alkyl, C 1 -C 4 straight or branched chain alkoxy, C 6 aryl, C 7-9 alkoxyaryl or C 6-10 heteroaryl.
The term " heteroaryl containing oxygen, sulfur or nitrogen as heteroatom " refers to a fully or partially unsaturated substituted monocyclic or poly (arylene) moiety containing carbon and hydrogen and at least one heteroatom Quot; means a cyclic carbon ring. The heteroatom is preferably oxygen or nitrogen, and most preferably nitrogen. The number of heteroatoms may be 1-4, 1-3, 1-2, or 1.
The term " heteroaryl " means a fully or partially unsaturated substituted cyclic carbon ring comprising carbon and hydrogen and at least one heteroatom (oxygen, sulfur or nitrogen). The heteroatom is preferably oxygen or nitrogen, and most preferably nitrogen. The number of heteroatoms may be 1-4, 1-3, 1-2, or 1.
According to one embodiment of the present invention, the
(1-1)
According to one embodiment of the present invention, R 1 and R 2 in
When R in formula (1) is alkoxy, the alkoxy may be substituted by various substituents, for example, halo, hydroxy, nitro, C 1 -C 4 substituted or unsubstituted straight or branched chain alkyl or C 1 - C 4 straight chain or branched chain alkoxy.
According to another embodiment of the present invention, R 1 in the general formula ( 1) is hydrogen or 6-Me; R 2 is 2'-Me, 3'4'- (OMe) 2 , 3'-Me, 2 ', 6'- (Me) 2 , 2'-OMe or 4'-OMe; R is OH, OMe or O (CH 2) 3 NMe 2 . According to a specific embodiment of the present invention, the diarylisoquinolone compound of
Meanwhile, the diarylisoquinoline compound of the present invention can be represented by the following Formula 2-1:
2-1
The topo inhibitory activity of the diarylisoquinoline compounds of the present invention depends on their chemical structure. Although 3,4-diarylisoquinolone generally did not inhibit topo I and had an inhibitory activity against topo Ⅱ, 3,4-diarylisoquinoline amine showed excellent topo I inhibitory activity. Isoquinoline amine derivatives have greater affinity for topo I than topo Ⅱ. Topo inhibition by 3,4-diarylisoquinoline amine is also supported by docking models. The docking model shows the intercalation and / or hydrogen bonding between the compounds of the present invention and DNA / topo. The association of these compounds with cytotoxicity and topo inhibition has revealed that the biological primary target of the compound derivative is topo, demonstrating that diaryl-substituted isoquinolines can be used as potent anticancer agents.
According to one embodiment of the present invention, R 1 and R 2 in Formula 2 are each independently hydrogen or C 1-2 alkyl; R is hydrogen, hydroxy or C 1-2 alkoxy, R 3 and R 4 are each independently hydrogen, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, C 6-10 aryl, C 6-10 Arylalkyl, C 6-10 arylalkoxy, C 4-5 heterocycloalkyl containing oxygen, sulfur or nitrogen as the heteroatom, C 6-10 heteroaryl containing oxygen, sulfur or nitrogen as the heteroatom; Or NR 3 R 4 is C 4-5 heterocycloalkyl containing oxygen, sulfur or nitrogen as the heteroatom or C 3-4 heterohazoles containing oxygen, sulfur or nitrogen as the heteroatom.
According to certain embodiments of the present invention, in
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a diarylisoquinolone or diarylisoquinoline compound of the present invention; And (b) a pharmaceutically acceptable carrier. The present invention also provides a pharmaceutical composition for preventing or treating cancer.
The pharmaceutical composition of the present invention is a composition comprising the compound of the present invention as described above, the contents of which are common between the two to omit the description thereof in order to avoid the excessive complexity of the present specification.
The composition of the present invention may be used for the treatment of breast cancer, prostate cancer, rectal cancer, stomach cancer, lung cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, colon cancer, cervical cancer, Thyroid cancer, pituitary cancer, ureteral cancer, and the like, but the present invention is not limited thereto. According to one embodiment of the present invention, the composition of the present invention exhibits cytotoxic and topo inhibitory effects in breast cancer, prostate cancer and rectal adenocarcinoma.
According to one embodiment of the present invention, the pharmaceutical composition of the present invention selectively inhibits the activity of topoisomerase I, topoisomerase II or topoisomerase I and II in cancer cells.
When the composition of the present invention is manufactured from a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).
The pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration or the like.
The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . The daily dosage of the pharmaceutical composition of the present invention is, for example, 0.001-1000 mg / kg. However, the actual dosage of the active ingredient may be determined taking into account various relevant factors such as the amount of neuron to be differentiated and proliferated, the route of administration, the weight of the patient, age and sex, And are not intended to limit the scope of the invention.
The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.
The features and advantages of the present invention are summarized as follows:
(a) The present invention relates to novel diarylisoquinolones or diarylisoquinolines compounds.
(b) The compounds of the present invention exhibit selective cytotoxicity in human cancer cells (T47D), human prostate cancer cell line (DU145) and human rectal adenocarcinoma cell line (HCT-15) And etoposide. ≪ / RTI >
(c) Furthermore, 3,4-diarylisoquinolone in the compounds of the present invention exhibits an inhibitory activity against topo II, 3,4-diarylisoquinoline amine exhibits excellent topo I inhibitory activity, Re-substituted isoquinoline can be used as an anticancer agent.
1 is an anticancer agent targeting topo.
Figure 2 is a 3-arylisoquinoline-based cytotoxic agent with topo inhibitory activity: 3-
3 shows 3,4-
4 shows by-products derived from arylboronic acid according to the Suzuki reaction.
Figure 5 shows the topo I inhibitory activity of 3,4-diarylisoquinolone. Lane D: pBR322 only; lane T: pBR322 + topo I; lane C: pBR322 + topo I + CPT; The remaining lanes: pBR322 + topo I + 3,4-diarylisoquinolone compounds.
Figure 6 shows the topo II inhibitory activity of 3,4-diarylisoquinolone. Lane D: pBR322 only; lane T: pBR322 + topo II; lane E: pBR322 + topo II + etoposide; The remaining lanes: pBR322 + topo II + 3,4-diarylisoquinolone compound.
Fig. 7 shows a coupled model (A) of the modified DNA-topo IIb complex and ethofoside and a virtual binding model of the modified DNA-topo IIb complex and
Figures 8A-8B show the topo I inhibitory activity of 3,4-diarylisoquinoline amines. Lane D: pBR322 only; lane T: pBR322 + topo I; lane C: pBR322 + topo I + CPT; The remaining lanes: pBR322 + topo I + 3,4-diarylisoquinoline amine.
Figures 9a-9b show topo II inhibitory activity of 3,4-diarylisoquinoline amines. Lane D: pBR322 only; lane T: pBR322 + topo Ⅱ; lane E: pBR322 + topo II + etoposide; The remaining lanes are: pBR322 + topo II + 3,4-diarylisoquinoline amine.
FIGS. 10A-10B show binding models (A, D) of topotecan and DNA and topo I; Virtual binding model of compound 6ba and DNA and topo I (B, E); And the virtual binding model (C, F) of the compound 6fd and the DNA and topo I. The carbon units of topotecan, compounds 6ba and 6fd are light green, nucleotides are purple, and amino acids are gray. The H-bond is indicated by the yellow dotted line.
Figure 11 depicts a virtual complex of DNA, modified topoII [beta] and compound 6dm. In the compound 6dm, the carbon unit was light blue, the nucleotide was purple, and the amino acid was gray. The H-bond is indicated by the yellow dotted line.
12 shows the SAR of 3,4-diarylisoquinoline.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
Example
Chemical synthesis
1. Retro synthesis
3,4-
<Synthetic scheme diagram 1. Initial synthesis scheme of 3,4-diarylisoquinolines 5 and 6>
Synthesis of 3,4-diarylisoquinolone
For the 3,4-diarylisoquinolone synthesis, the coupling reaction of toluamide 10a and o-tolunitrile 11a was carried out in the presence of n-BuLi to provide 3-arylisoquinolone 9a (Scheme 2). (NBS) and 1,10-azobis (cyclohexanecarbonyl) (ACCN) treatment in the presence of light resulted in regioselective bromination at the C4 position of 9a to give compound 8a Is obtained. Palladium catalyst [Ti Tra tetrakis (triphenylphosphine) palladium (0) (Pd (PPh 3 ) 4 (0))] in the presence, aryl bromide due to the Suzuki reaction of Nick acid bromide, 4-isopropyl quinolone 8a, a
<
Reagents and reaction conditions: (i) n-BuLi, dry THF, -78 ° C; (ii) NBS, ACCN,
≪
Reagents and reaction conditions: (i) ArB (OH) 2 , Pd (PPh 3 ) 4 (0), Na 2 CO 3 , (MeOCH 2 ) 2 , 90 ° C.
<
Reagents and reaction conditions: (i) POCl 3 , 75 ° C; (ii) ArB (OH) 2 , Pd (PPh 3 ) 4 (0), Na 2 CO 3 , (MeOCH 2 ) 2 , 90 ° C.
Synthesis diagram 5. Retro-synthesis of 3,4-
3. 3,4- Diarylisoquinolone synthesis
O-methylation of isoquinolone 8 predominantly occurred in the presence of Ag 2 CO 3 , and 3-aryl-4-bromo-1-
4. 3,4- Diarylisoquinoline amine synthesis
The 3,4-
<
Reagents and reaction conditions: (i) F 3 CCOOH, CH 2 Cl 2 , reflux.
Also, the hydroxyphenyl-substituted 3,4-diarylisoquinoline 14a 'reacts with an alkyl halide containing the amino end in the presence of K 2 CO 3 as a base to give 3,4-diarylisoquinoline 18 Scheme 7). The lactam group of compound 18 is finally hydrolyzed to the lactam under acidic conditions to produce
≪ Synthetic scheme 7. Modification of hydroxyphenyl-substituted 3,4-diarylisoquinoline 14a '
Reagents and reaction conditions: (i) Cl (CH 2 ) 3
Biological measurement
1. Cytotoxicity
The cytotoxic effect of the synthesized 3,4-diarylisoquinolones (5 and 19) and 3,4-diarylisoquinoline amines (6 and 17) was measured by MTT. MTT assays were performed using noncancerous human mammary epithelial cell line (MCF10A), human carcinoma epithelial carcinoma cell line (T47D), human prostate cancer cell line (DU145) and human rectal adenocarcinoma cell line (HCT-15) [16]. Cytotoxicity measurements were expressed as IC50 (Tables 1 and 3-5).
2. Topo control
The topo inhibitory activity of 3,4-diarylisoquinolone and 3,4-diarylisoquinoline amine was measured using DNA relaxation assay (FIGS. 5, 6, 8 and 9) [16]. In this experiment, topo uncovers supercoiled plasmids, resulting in a difference in mobility between fully annealed DNA and electrophoresis. The topo inhibitory activity of a compound is determined by measuring the degree of supercoiled plasmid. DNA relaxation assays were performed using topo I / IIa and plasmid pBR322, and CPT and etoposide were used as positive controls for topo I and II inhibition, respectively. Assays were performed in the presence of 20 mM or 100 mM of the positive control or the test compound. The topo inhibitory effect by the test compound was expressed in% (Table 2, 6-8). The relative topo inhibitory activity of diarylisoquinolines was determined as the topo inhibition ratio of each compound to the topo inhibition ratio of CPT / etoposide in SAR studies. Each compound is classified according to the following criteria: 0.0-0.25 (inactive),> 0.25-0.5 (low activity),> 0.5-0.8 (usually active),> 0.8e1.0 (activity similar to CPT / etoposide), and > 1.0 (activity superior to CPT / etoposide).
3. Docking
In order to study the interactions associated with topo suppression, a hypothetical coupled model of DNA-topo I / II complexes and diaryl-substituted isoquinoline derivatives was constructed using a molecular docking tool. The ligand was removed from the three-dimensional crystal structure of the DNA-topo-ligand using the Surflex-Dock program Sybyl-X 2.0 (winnt_os5x), and the resulting pores were docked with diarylisoquinoline. To study topo I inhibition, DNA-topo I-topotecan complex (PDB: 1K4T) was used [17]. However, due to the lack of crystal structure of the DNA-topo IIα ligand, the DNA-topo IIβ-ethoposide (PDB: 3QX3) tertiary complex was modified for docking [18]. Only two amino acids are different in the etoposide-binding pocket of topo IIa and topo IIb. Met762 and Ser800 of topo Ⅱα are replaced by Gln778 and Ala816, respectively, in topo Ⅱβ. Thus, Gln778 and Ala816 of 3QX3 are transformed into Met and Ser according to the possible parameters in the crystal structure of DNA-topo IIα (PDB: 4FM9) [19].
Experimental results and discussion
1. 3,4- Diarylisoquinolone
3,4-diarylisoquinolones, 5a, 5c, and 5f showed selective cytotoxicity in tumor cell T47D and non-toxicity in MCF-10A cell line, which is normal cell (Table 1). Similarly,
Each value represents the mean ± SD of 3 repeated experiments. a MCF-10A; b T47D; c DU145; d HCT-15.
3,4-Diarylisoquinolone showed toxicity in human rectal cancer cells (HCT-15).
3,4-Diarylisoquinolones generally do not inhibit topo I (Table 2, Figures 5 and 6).
Each value represents the mean ± SD of 3 repeated experiments. ND: Not determined. a
Despite topos inhibitory activity, 5g has low cytotoxicity; This may be because the physicochemical properties of the compound interfere with cell penetration and cause intracellular diffusion or the cellular metabolism breaks down before the compound reaches the topo. On the other hand, cytotoxic compounds such as 5a ', 5b, 5c, 5e and 19 show effects through other mechanisms. The normal topo inhibitory activity and strong cytotoxicity of
Using a molecular docking tool, we constructed a virtual binding model of 3,4-
2. 3,4- Diarylisoquinoline amine
The proliferation inhibitory activity of 3,4-diarylisoquinoline amines in human cell lines (MCF-10A, T47D, DU145 and HCT-15) is determined by the type of amine substituted at the C1 position (Table 3 and Table 4). Isoquinolones with aromatic amine (h), aromatic heterocyclic amines (e, f and g) and secondary amines (l, m, n and o) do not generally affect cell viability. In the cytotoxicity profile experiments, 6an, 6ef, and 6gf isoquinoline amines were not toxic to the four cell lines. Similarly, p-methoxybenzylamine-substituted isoquinolines (6bm, 6em, 6fm, and 6gm) did not show cytotoxicity. However, the 6am and 6dm derivatives showed strong cytotoxicity in T27 cells. In addition, the 6ee compound showed selective toxicity to T47D cells (IC 50 : 11.7 + 0.4 mM). On the other hand, compound 6cl showed selective toxicity to HCT-15 cells (IC 50 : 6.48 + 0.34 mM). The aniline- (6co), imidazole- (6eh) and isoquinoline-substituted (6fg) derivatives did not show toxicity in MCF-10A and DU145 cells and showed proliferation inhibition on T47D and HCT-15 cells IC 50 : 13.5 ± 0.22-2.06 ± 0.1 mM). The secondary 3,4-diarylisoquinoline amine 6ei showed selective toxicity to T47D and HCT-15 cells, whereas the compounds 6ai, 6aj and 6bk were not toxic to T47D, and DU145, HCT-15 and MCF-10A Cells were toxic. Piperazine substituted isoquinoline amines (ad) were generally more toxic than compounds substituted with other amines. Piperazinyl ethanamine 6ad is the strongest cytotoxic compound among the isoquinolines tested in T47D cells (IC 50 : 0.05 ± 0.003 mM) and HCT-15 cells (IC 50 : 0.08 ± 0.001 mM). However, these compounds also showed toxicity in the normal cell, MCF-10A. The primary 3,4-diarylisoquinoline amine 17 showed normal or low cytotoxicity in MCF-10A cells (IC 50 : 14.9 ± 0.08-42.0 ± 0.1, Table 5). The primary isoquinoline amine (except 17e) did not show toxicity to the cancer cell T47D. Similarly, isoquinoline amine 17 exhibited a normal low proliferation inhibitory effect in DU145 cells (IC 50 : 10.8 ± 0.03-44.8 ± 0.89). An important feature of these compounds is that they have higher cytotoxicity than HCT-15 cells, CPT, etoposide and DOX (IC 50 : 2.8 ± 0.05-0.78 ± 0.02).
Each value represents the mean ± SD of 3 repeated experiments. a MCF-10A; b T47D; c DU145; d HCT-15.
Each value represents the mean ± SD of 3 repeated experiments. a MCF-10A; b T47D; c DU145; d HCT-15.
Each value represents the mean ± SD of 3 repeated experiments. a MCF-10A; b T47D; c DU145; d HCT-15.
3,4-Diarylisoquinoline amine exhibits strong topo I inhibitory activity (Tables 6 and 7, FIG. 8). Piperazinyl- (6ad, 6ba, 6ed, 6fd, and 6ga), methoxyphenylpiperazinyl-6ee, pyrimidinylpiperazinyl-6f, isoquinolinyl-6fg and benzyl- Or an equivalent topo inhibitory effect. Among the above derivatives, compounds 6ee and 6fd show a topo I inhibitory effect at a relatively low concentration (20 mM). 3,4-Diarylisoquinoline amines do not inhibit topo II (Table 6 and Table 7, Figure 9). 6 gm of multiarylisoquinoline amine exhibits a topo II inhibitory activity similar to that of ethobocyte and exhibits a normal topo I inhibitory effect. The topo Ⅱ inhibitory activity of 6 dm was 86% of the etoposide at 100 mM concentration. The
Each value represents the mean ± SD of 3 repeated experiments. ND: Not determined. a compound 6a series, 6co, and 6 cl; b Compounds 6b and 6d series and 6cc; c The parentheses indicate the relative topoisomerase activity (topo inhibitory activity of the compound / CPT or topo inhibitory activity of etoposide).
Each value represents the mean ± SD of 3 repeated experiments. ND: Not determined. a compound 6e series and 6 gm; b Compounds 6f series, 6ga, 6gb, and 6gf; c The parentheses indicate the relative topoisomerase activity (topo inhibitory activity of the compound / CPT or topo inhibitory activity of etoposide).
Each value represents the mean ± SD of 3 repeated experiments. ND: Not determined. a
Although 3,4-diarylisoquinoline amines (6ef and 6fm) strongly inhibited topo I and topo Ⅱ, they showed non-toxicity in human cell lines. However, there was a strong correlation between cytotoxicity and topo inhibition in the remaining topo inhibitors. In the coupled model by docking, it can be seen that the isoquinolin ring of compound 6ba overlaps with the DNA base of the scissile strand, which exhibits a pi-pi stacking action between aromatic rings (B in Figure 10a, E in Figure 10b). Compound 6ba interacted with topo I Arg364 and Thr718 by hydrogen bonding. A similar interaction with 6ba was found between 6fd, DNA base and Arg364 of topo I (C in Figure 10a, F in Figure 10b). Furthermore, 6fd formed a hydrogen bond with the DNA cytosine base. 6 dm of secondary isoquinoline amine was hydrogen bonded to Asp479 of topo Ⅱ. However, it did not interact with DNA (π-π stacking / hydrogen bonding) (Fig. 11).
The π-π stacking interactions of species inserted into the gap of the DNA base pair suppress topo activity [17]. The topo inhibitor is inserted between the nucleotides to destroy the DNA structure, the reactive base of -1 base prevents the topo attached to the covalent bond from dropping to the + 1 base, and the cleaved DNA strands are bound by transesterification I can not. In addition, hydrogen bonding that interacts with the Arg364 amino acid of topo I is essential for topo I inhibitory activity, which is common in topo I inhibitors such as CPT, indenoisoquinoline (MJ238) and indolocarbazole (SA315F) [23 ]. Important in interaction with Arg364 is that CPT and indolocarbazole exhibit low binding for topo I with the Arg364His mutation. As a result, DNA-topo complexes and 6ba, 6fd and 6dm docking models confirmed strong topo inhibitory activity.
3. SAR of 3,4-diarylisoquinoline
The cytotoxicity and topo inhibitory activity of 3,4-diarylisoquinolone and 3,4-diarylisoquinoline amine depend on the specific structure of the compound (FIG. 12). When aromatic rings are added to the 3-aryl group of 3,4-diarylisoquinolone, they exhibit strong inhibitory activity against topo I and II. It is not advantageous if the 3 " -OMe of 4-aryl is replaced by -OH and -O (CH 2 ) 3 NMe 2 , and the toxicity of non-toxic derivatives to non-cancerous MCF- Respectively. 3,4-Diarylisoquinolone with 6,2 '- (Me) 2 did not decrease the proliferation of HCT-15.
The conversion of isoquinolone to isoquinoline amine significantly changes the cytotoxicity and topo inhibitory activity. In general, 3,4-diarylisoquinoline amines exhibit greater cytotoxicity than 3,4-diarylisoquinolones and more efficiently inhibit topo. Interestingly, 3,4-diarylisoquinoline amines do not have a methyl substituent at the C6 position and exhibit superior topo I inhibitory activity than the 6-Me derivatives, regardless of the amine and other substituents (Table 6 and Table 7). The piperazine-substituted analogs exhibited the best cytotoxic profile among all isoquinolines. The primary isoquinoline amines were more toxic than the other isoquinolines in normal MCF-10A cells. However, these compounds did not show toxicity at T47D. Conversion of isoquinolone to primary isoquinoline amine increases the topo inhibitory effect. However, isoquinoline amines substituted by aromatic amines (imidazoles) and amines containing aromatic moieties showed low cytotoxicity. Similarly, 1,3,4-triarylisoquinoline amine showed no toxicity in all cell lines and no topo inhibitory activity.
conclusion
The development of alternative topo inhibitors is required due to the limitations of Topo inhibitors targeting Topo. Of the many compounds developed as topo inhibitors, 3-aryl isoquinoline derivatives are promising. Monoaryl-substituted isoquinolines, 3,4-diarylisoquinolones and 3,4-diarylisoquinoline amines were designed and synthesized based on SAR studies to evaluate their cytotoxicity and topo inhibitory activity. Some of the compounds of the present invention showed cytotoxicity at a sub-mM concentration, showed selective toxicity to cancer cells, and correlated with cytotoxicity and topo inhibition. This suggests that diaryl substituted isoquinolines are likely to be developed as safer cancer treatments.
Experimental Method
Compound synthesis
The melting point (mp) was determined by the capillary method using the MEL-TEMP® 3.0 device and was found to be inaccurate. 1 H NMR and 13 C NMR spectra were measured on a Varian Unity Plus 300 MHz and Varian Unity Inova 500 MHz spectrometer (Korea Basic Science Institute). Spectral data were recorded in the following order: chemical shift, multiplicity (s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, b: broad, bs: broad singlet, dd: doublet of doublets, dt: doublet of doublets, td: triplet of doublets, ddd: doublet of doublets of doublets), coupling constant, number of protons and number of protons. Chemical shifts were recorded per ppm downfield relative to TMS (tetramethylsilane, d ¼ 0). Coupling constant, and J is expressed in hertz (Hz). Mass spectra were obtained on a Shimadzu LCMS-2010 EV liquid chromatography mass spectrometer using the electron spray ionization (ESI) method. High resolution mass spectra were obtained with a Waters Synapt G2 High Definition Mass Spectrometer. Column chromatography and MPLC (medium performance liquid chromatography; Yamazen) were performed at a flow rate of 10 mL / min using Merck silica gel 60 (70-230 mesh). Thin film chromatography (TLC) was performed using plates coated with silica gel 60 F254 (Merck). Chemical reagents were purchased from Sigma-Aldrich and Tokyo Chemical Industry Co., Ltd. The solvent was distilled before use; Tetrahydrofuran (THF) was distilled from sodium / bentophenone. All reactions were carried out in a dried glassware under a nitrogen atmosphere.
1. 6-Methyl-3- (o-tolyl) isoquinolin-1 (2H) -one (9a)
Oven dried, three flasks were sealed and nitrogen was injected three times before the reaction. A mixture of hexane-less 2.5 M n-BuLi (38 mL, 95.9 mmol) and dry THF (35 mL) was reacted at 70 ° C or lower and N, N-diethyl-2,4-dimethylbenzamide (10a; 38.4 mmol) and o-tolunitrile (11a; 6.74 g, 57.5 mmol) were added and reacted at 60 ° C or lower. The reaction mixture was stirred at 78 ° C for 14 hours, allowed to cool to room temperature, quenched with water and extracted with CHCl 3 . The organic layer was washed with water and concentrated. The EtOAc-insoluble fraction was separated off and washed with EtOAc to give compound 9a as a white solid (3.98 g, 41%). The filtrate was applied to column chromatography (n-hexane: EtOAc ¼ 5: 1, 1: 1) to give a yellow mass containing compound 9a (2.79 g). 1 H NMR (300 MHz, DMSO-d 6)? (Ppm): 11.30 (s, 1H, NH), 8.08 (d, J = 8.1 Hz, ), 7.39-7.25 (m, 5H, Ar-H), 6.39 (s, 1H, 4-H), 2.43 (s, 3H, Ar-CH3), 2.29 (s, 3H, Ar-CH3). MS (ESI): m / z 250 (M + H) < + >, 272 (M + Na) < + >.
2-Bromo-6-methyl-3- (o-tolyl) isoquinolin-1 (2H)
The CCl 4 (10 mL) under a compound 9a (1 g, 4.01 mmol) NBS (1.07 g, 6.01 mmol) and 98% ACCN (250 mg, 1 mmol) was added. The reaction mixture was refluxed for 2 hours using a sand bath, then water was added and extracted with CH 2 Cl 2 . Breen (saturated NaCl solution), and with anhydrous Na 2 SO 4 and dried the organic film, and concentrated. The residue was purified by column chromatography (n-hexane:
(3-hydroxyphenyl) -6-methyl-3- (o-tolyl) iroquinolin-1 (2H)
After the compound 8a (200 mg, 0.61 mmol) was dissolved in 1,2-dimethoxyethane (10 mL), 3-hydroxyphenyl boronic acid (168 mg, 1.22 mmol) was added in the presence of MeOH 3 ) 4 (0) (35 mg, 0.03 mmol) and sat. Na 2 CO 3 sol. (5 mL) was added. The reaction mixture was heated at 90 degrees for 23 hours and then filtered through a celite bed. Filtered, extracted with EtOAc and water, and Dublin with anhydrous Na 2 SO 4 and dried the organic film, and concentrated. The residue was purified by MPLC (nhexane: CH 2 Cl 2 ¼ 5: 1) to give
4. 3- (3,4-Dimethoxyphenyl) -6-methylisoquinolin-1 (2H) -one (9b)
Oven dried, three flasks were sealed and nitrogen was injected three times before the reaction. A mixture of hexane-less 2.5M n-BuLi (35 mL, 87.6 mmol) and dry THF (20 mL) was reacted below 70 ° C and N, N-diethyl-2,4-dimethyl Benzamide (10a; 6 g, 29.2 mmol) and 3,4-dimethoxybenzonitrile (11b; 7.15 g, 43.8 mmol) were added and reacted in 60 ° C in dry THF (7 mL). The reaction mixture was stirred at 78 ° C for 38.5 hours, allowed to stand at room temperature, and then the reaction was terminated with water. The precipitate was removed and washed with water and ethanol to give compound 9b, a white solid. The filtrate was extracted with CH 2 Cl 2 , washed with water and concentrated. The ethanol-insoluble fraction was again filtered off and washed with ethanol to give the final compound 9b (6.46 g, 74%). 1H NMR (300 MHz, DMSO-d6) d (ppm): 11.34 (s, IH, Ar-H), 8.07 (d, J = 8.1 Hz, H), 6.81 (s, 1H, Ar-H), 7.37-7.34 (m, 2H, Ar-H), 7.29-7.26 , 4-H), 3.87 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 2.43 (s, 3H, 6-CH3). MS (ESI): m / z 296 (M + H) +, 337 (M +
5. 4-Bromo-3- (3,4-dimethoxyphenyl) -6-methylisoquinolin-1 (2H)
The compound 9b (5.52 g, 18.7 mmol), NBS (4.99 g, 28.1 mmol), 98% ACCN (1.16 g, 4.67 mmol) and CHCl 3 (40 mL) Chromatography (n-hexane: EtOAc ¼ 5: 1) afforded compound 8b as a light yellow solid (5.73 g, 81%). Rf 0.14 (nhexane:
6. 4-Bromo-l-chloro-6-methyl-3- (o-tolyl) isoquinoline (12a)
A solution of compound 8a (1.21 g, 3.68 mmol) in the presence of POCl 3 (20 mL) was heated at 75 ° C. and excess POCl 3 and volatiles were removed by vacuum distillation. Saturated NaHCO 3 solution (100 mL) was added to the resultant and extracted with ethanol. Washing an organic layer with water and concentrated after drying the organic film using anhydrous Na 2 SO 4. The residue was purified by column chromatography (n-hexane:
7. 4-Bromo-1-chloro-3- (3,4-dimethoxyphenyl) -6-methylisoquinoline (12b)
Compound 8b (660 mg, 1.84 mmol) and POCl 3 (15 mL) were used in the above procedure of Compound 12a and column chromatography (n-hexane: EtOAc ¼ 5: 1) gave Compound 12b as a light yellow solid (649 mg, 93%). 1H, NMR (300 MHz, CDCl3) d (ppm): 8.24 (d, J = 8.7 Hz, 1H, Ar-H), 8.14 , Ar-H), 7.36-7.32 (m, IH, Ar-H), 7.28 (d, J = 1.8 Hz, , 3.95 (s, 6H, OCH3), 2.64 (s, 3H, 6-CH3).
8. Preparation of 1,4-bis (3-methoxyphenyl) -6-methyl-3- (o-tolyl) isoquinoline (13a)
A solution of 3-methoxyphenyl boronic acid (688 mg, 4.54 mmol) and Pd (PPh 3 ) 4 (0) (131 mg, 0.78 mmol) in the presence of compound 12a (785 mg, 2.26 mmol) and MeOH , 0.11 mmol), saturated Na 2 CO 3 solution (5 mL) and 1,2-dimethoxyethane (15 mL) were used, and MPLC (n-hexane:
9. 3,3 '- (3- (3,4-Dimethoxyphenyl) -6-methylisoquinoline-1,4-diyl)
A solution of 3-aminiphenylboronic acid monohydrate (206 mg, 1.32 mmol) and Pd (PPh 3 ) 4 (0) (31 mg, 0.02 mmol) in the presence of 5 mmol of the compound 12b (200 mg, 0.53 mmol) mmol), saturated Na 2 CO 3 solution (2 mL) and was performed using the 1, 2-dimethoxyethane (12 mL), MPLC (nhexane : EtOAc ¼ 5: 1, 4: 1, 3: 1, 1: 1 ) To give compound 13b in the form of a brown semisolid (115 mg, 46%). Rf 0.45 (n-hexane:
10. 6-Methyl-3- (m-tolyl) isoquinolin-1 (2H) -one (9c)
(3.99 g, 34.1 mmol), m-tolunitrile 11c (2.5 g, 34.1 mmol) and N, N-diethyl-2,4-dimethylbentamide 10a (4.66 g, 22.7 mmol) Filter and column chromatography (n-hexane:
11. 3- (2,6-Dimethylphenyl) -6-methylisoquinolin-1 (2H) -one (9d)
(2 g, 9.74 mmol), 2,6-dimethylbenzonitrile 11d (1.91 g, 14.6 mmol) in the presence of hexane and 2.5 M of N, N-diethyl-2,4-dimethylbentamide 10a Column chromatography (n-hexane: EtOAc ¼ 5: 1, 3: 1) was performed using n-BuLi (10 mL, 24.3 mmol) and dry THF (35 mL) To give compound 9d (2.63 g). The compound 9d is a white solid. (D, J = 8.1 Hz, 1H, 8-H), 7.42 (s, 1H, 5-H) , 7.31 (dd, J = 8.1, 1.2 Hz, 1H, Ar-H), 7.27-7.22 (m, 1H, Ar-H), 7.15-7.12 1H, 4-H), 2.43 (s, 3H, 6-CH3), 2.14 (s, 6H, 20, 60- (CH3) 2).
12. 3- (2-Methoxyphenyl) isoquinolin-1 (2H) -one (9e)
(7.3 g, 54.8 mmol), 2.5 M n-BuLi (1 ml) solution in hexane, and a solution of the compound (N-hexane:
13. 3- (4-Methoxyphenyl) isoquinolin-1 (2H) -one (9f)
(3.29 g, 17.2 mmol), 4-methoxybutanenitrile 11f (3.43 g, 25.8 mmol), 2.5 M n-BuLi in the presence of hexane (17 mL, 43 mmol) and dry THF (35 mL) to give compound 9f as a white solid (2.86 g, 66%). Compound 9f is a known compound [24].
14. Preparation of 4-bromo-6-methyl-3- (m-tolyl) isoquinolin-1 (2H)
The compound 9c (1.98 g, 7.95 mmol), NBS (2.12 g, 11.9 mmol), 98% ACCN (496 mg, 1.99 mmol) and CHCl 3 (30 mL) Through recrystallization, white solid compound 8c was obtained (2.02 g, 77%). (D, J = 8.1 Hz, 1H, 8-H), 7.84 (s, 1H, 5-H), 7.40 (M, 4H, Ar-H), 7.32-7.30 (m, 1H, Ar-H), 2.56 (s, 3H, Ar-CH3), 2.44 (s, 3H, Ar-CH3).
15. Preparation of 4-bromo-3- (2,6-dimethylphenyl) -6-methylisoquinolin-1 (2H)
The compound 9d (2.32 g, 8.80 mmol), NBS (2.35 g, 13.2 mmol), 98% ACCN (549 mg, 2.20 mmol) and CHCl 3 (30 mL) Chromatography (n-hexane: EtOAc ¼ 5: 1, 1: 1) yielded compound 8d as a light orange solid (2.97 g, 98%). Rf ¼ 0.5 (n-hexane: EtOAc ¼ 1: 1). (D, J = 8.1 Hz, 1H, 8-H), 7.68 (s, 1H, 5-H) , 7.44 (ddd, J = 8.1, 1.5, 0.6 Hz, 1 H, Ar-H), 7.30-7.25 (m, 1H, Ar-H), 7.18-7.16 , overlapped with the DMSO peaks), 2.09 (s, 6H, 20, 60- (CH3) 2).
16. 4- Bromo -3- (2- Methoxyphenyl ) Isoquinolin-1 (2H) -one (8e) and 3-aryl-4- Bromoisoquinoline -1 (2H) -one (8 g)
(5.80 g, 23.1 mmol), NBS (6.16 g, 34.6 mmol), 98% ACCN (1.44 g, 5.77 mmol), and CHCl 3 (25 mL) 8e and 8g (5.72 g). Rf ¼ 0.37 (nhexane: EtOAc ¼ 1: 1). (M, 2H, Ar-H), 8.06-8.01 (m, 2H), 8.09 (bs, 2H, Ar-H), 7.82-7.76 (m, 2H, Ar-H), 7.60-7.54 (m, 4H, Ar-H), 7.52-7.40 1H, Ar-H), 3.81 (s, 3H, OCH3), 7.01 (d, J = 8.4 Hz, 3.79 (s, 3H, OCH3). 8e: MS (ESI) m / z 330 (MH) - (81Br), 328 (MH) - (79Br). 8 g: MS (ESI): m / z 408 (MH) - (79 Br, 81 Br), 406 (MH) - (79 Br), 410 (MH) - (81 Br).
17. 4-Bromo-3- (4-methoxyphenyl) isoquinolin-1 (2H) -one (8f)
The compound 9f (3.44 g, 13.7 mmol), NBS (3.65 g, 20.5 mmol), 98% ACCN (837 mg, 3.35 mmol) and CHCl 3 (40 mL) (N-hexane: EtOAc ¼ 4: 1, 1: 1) to give compound 8f as a white solid (4.21 g, 93%). Mp: 199-204 ° C. 1H, NMR (300 MHz, DMSO-d6) d (ppm): 11.73 (s, 1H, NH), 8.28-8.25 (M, 2H, 30-H and 50-H), 3.82 (s, 1H, Ar-H), 7.49-7.45 , 3H, OCH3).
18. 4-Bromo-1-methoxy-6-methyl-3- (o-tolyl) isoquinoline (15a)
To the mixture of compound 8a (1.47 g, 4.49 mmol) in the presence of toluene (25 mL) was added silver carbonate (1.11 g, 4.04 mmol) and iodomethane (765 mg, 5.39 mmol). After the reaction mixture was heated to 90 ° under dark conditions, water was added to terminate the reaction and extracted with ethanol. An organic film was concentrated after drying with Brin and anhydrous Na 2 CO 3. The product was purified by column chromatography (nhexane:
19. 4-Bromo-3- (3,4-dimethoxyphenyl) -1-methoxy-6-methylisoquinoline (15b)
The compound 8b (4.93 g, 13.2 mmol), iodomethane (2.8 g, 19.7 mmol), silver carbonate (3.27 g, 11.8 mmol) and toluene (30 mL) (n-hexane:
20. Preparation of 4-bromo-1-methoxy-6-methyl-3- (m-tolyl) isoquinoline (15c)
The compound 8c (1.44 g, 4.41 mmol), iodomethane (939 mg, 6.61 mmol), silver carbonate (1.09 g, 3.97 mmol) and toluene (20 mL) hexane:
21. 4-Bromo-3- (2,6-dimethylphenyl) -1-methoxy-6-methylisoquinoline (15d)
The compound 8d (2.89 g, 8.46 mmol), iodomethane (1.8 g, 12.6 mmol), silver carbonate (2.09 g, 7.61 mmol) and toluene (25 mL) (n-hexane:
22. 4- Bromo -One- Methoxy -3- (2- Methoxyphenyl ) Isoquinoline (15e) and 3-aryl-4- Bromo -One- Methoxyisoquinoline (15 g)
(N-hexane: EtOAc) was used as the above-mentioned compound 15a and Compound 8e and 8g (4.99 g), iodomethane (3.22 g, 22.7 mmol), silver carbonate (3.75 g, 13.6 mmol) and toluene. 5: 1, 3: 1) to give a mixture of 15e and 15g which is a white solid (4.7g). Rf 0.48 (n-hexane:
23. Preparation of 4-bromo-1-methoxy-3- (4-methoxyphenyl) isoquinoline (15f)
The compound 8f (3.41 g, 10.3 mmol), iodomethane (2.2 g, 15.5 mmol), silver carbonate (1.68 g, 6.1 mmol) and toluene (30 mL) were subjected to column chromatography n-hexane: EtOAc ¼ 4: 1, 3: 1) to give compound 15f as a white solid (3.19 g, 89%). Rf ¼ 0.28 (nhexane: CH2Cl2 ¼ 5: 1). 1H NMR (300 MHz, DMSO-d6)? (Ppm): 8.25-8.17 (m, 2H, Ar-H), 7.97-7.91 3H, OCH3), 3.83 (s, 3H, OCH3), 7.07-7.02 (m, 2H, 30-H and 50-H).
24. 1-Methoxy-4- (3-methoxyphenyl) -6-methyl-3- (o-tolyl) isoquinoline (14a)
The compound 15a 15a processes and compounds of the '(891 mg, 2.60 mmol) , MeOH (4 mL) the presence of 3-methoxyphenylboronic acid (791 mg, 5.20 mmol) solution, Pd (PPh 3) 4 ( 0) (150 mg, 0.13 mmol), saturated Na 2 CO 3 solution (3 mL) and 1,2-dimethoxyethane (15 mL) and column chromatography (n-hexane:
25. 3- (3,4-Dimethoxyphenyl) -1-methoxy-4- (3-methoxyphenyl) -6-methylisoquinoline (14b)
A solution of 3-methoxyphenylboronic acid (3.16 g, 20.8 mmol) and Pd (PPh 3 ) 4 in the presence of compound 15b (4.03 g, 10.4 mmol) and MeOH (8 mL) (352 mg, 0.3 mmol), saturated Na 2 CO 3 solution (5 mL) and 1,2-dimethoxyethane (30 mL) were used, and MPLC (nhexane:
26. 1-Methoxy-4- (3-methoxyphenyl) -6-methyl-3- (m- tolyl) isoquinoline (14c)
A solution of 3-methoxyphenylboronic acid (1.6 g, 10.5 mmol) and Pd (PPh 3 ) 4 in the presence of compound 15c (1.73 g, 5.07 mmol) and MeOH (N-hexane:
27. 3- (2,6-Dimethylphenyl) -1-methoxy-4- (3-methoxyphenyl) -6-methylisoquinoline (14d)
A solution of 3-methoxyphenylboronic acid (2.22 g, 14.6 mmol) and Pd (PPh 3 ) 4 in the presence of compound 15d (2.61 g, 7.32 mmol) and MeOH (10 mL) (423 mg, 0.36 mmol), saturated Na 2 CO 3 solution (5 mL) and 1,2-dimethoxyethane (25 mL), and subjected to column chromatography (n-hexane:
28. Methoxy-3- (2-methoxyphenyl) -4- (3-methoxyphenyl) isoquinoline (14e)
A solution of 3-methoxyphenylboronic acid (4.08 g, 26.86 mmol) and Pd (PPh 3 ) 4 (15 g) in the presence of 15a and 15 g (4.62 g) (0) (776 mg, 0.67 mmol), saturated Na 2 CO 3 solution (5 mL) and 1,2-dimethoxy ethane was used (35 mL), MPLC (nhexane : CH 2 C l2 ¼ 12: 1, 10: 1, 5: 1) to give 14 g of a white solid compound 14e (2.4 g) and 14 g of a yellow viscous liquid form compound (1.89 g). Rf 0.56 (nhexane:
29. 3-Aryl-1-methoxy-4- (3-methoxyphenyl) isoquinoline (14 g)
Rf 0.43 (n-hexane:
30. Preparation of 1-methoxy-4- (3-methoxyphenyl) -3- (4-methoxyphenyl) isoquinoline (14f)
A solution of 3-methoxyphenylboronic acid (1.81 g, 11.9 mmol), Pd (PPh 3 ) 4 (5 g) in the presence of the compound 15a (3.06 g, 8.89 mmol) and MeOH (N-hexane: EtOAc ¼ 5: 1, 3: 1) (514 mg, 0.44 mmol), saturated Na 2 CO 3 solution (5 mL) and 1,2- : Compound 1f, which was a transparent viscous liquid, was isolated (265 mg, 8%) to obtain compound 14f containing impurities.
Then, a solution of 3-methoxyphenylboronic acid (1.61 g, 10.6 mmol) and Pd (PPh 3 ) 4 in the presence of compound 15a (1.83 g, 5.31 mmol) and MeOH (0) (307 mg, 0.26 mmol), saturated Na 2 CO 3 solution (5 mL) and 1,2-dimethoxyethane (20 mL). The impure compound 14f (2.16 g) was obtained by the above two-step reaction. (M, 2H, 20-H), 7.60-7.47 (m, 3H, Ar-H), 7.44-7.39 2H, 30-H and 50-H), 4.21-7.27 (m, 3H, Ar-H), 7.32-7.27 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.74 (s, 3H, OCH3). MS (ESI): m / z 372 (M + H) < + >.
31. 3- (1-Methoxy-6-methyl-3- (o-tolyl) isoquinolin-
A solution of hydroxyphenylboronic acid (795 mg, 5.76 mmol) in the presence of compound 15a (986 mg, 2.88 mmol) and MeOH (5 mL) and Pd (PPh 3 ) 4 (N-hexane: EtOAc 5: 1: 1) (166 mg, 0.14 mmol), saturated Na 2 CO 3 solution (5 mL), and 1,2-dimethoxyethane ) To give a fluffy white crystalline compound 14a '(650 mg, 63%). 1H, Ar-H), 7.49-7.46 (m, 1H, Ar-H), 8.16 (d, J = 8.4 Hz, H), 6.63-6.54 (m, 3H, Ar-H), 7.20 (s, 1H, Ar-H), 7.15-7.04 Ar-H), 4.01 (s, 3H, OCH3), 2.38 (s, 3H, Ar-CH3), 2.14 (s, 3H, Ar-CH3). MS (ESI): m / z 356 (M + H) < + >.
32. 4- (3-Methoxyphenyl) -6-methyl-3- (o-tolyl) isoquinolin- 1 (2H)
A mixture of compound 14a (904 mg, 2.44 mmol) and AcOH: H 2 O ¼ 9: 1 (10 mL) was refluxed for 39 hours. Saturated NaHCO 3 solution (100 mL) was used to neutralize excess AcOH and extracted with CH 2 Cl 2 . The organic layer was washed with water, concentrated under reduced pressure, and purified by methanol recrystallization to obtain a white
33. 3- (3,4-Dimethoxyphenyl) -4- (3-methoxyphenyl) -6-methylisoquinolin- 1 (2H)
(N-hexane: EtOAc ¼ 3: 1, EtOAc) was used as the starting material for the
34. 4- (3-Methoxyphenyl) -6-methyl-3- (m-tolyl) isoquinolin- 1 (2H)
(N-hexane: EtOAc ¼ 5: 1, EtOAc), using Compound 14c (1.60 g) and AcOH: H 2 O ¼ 9: 1 (10 mL) To give a fluffy white
35. 3- (2,6-Dimethylphenyl) -4- (3-methoxyphenyl) -6-methylisoquinolin- 1 (2H)
Compound 18d (1.48 + 1.6 g) and AcOH: H 2 O ¼ 9: 1 (20 + 20 mL) containing the
36. 3- (2-Methoxyphenyl) -4- (3-methoxyphenyl) isoquinolin-1 (2H)
Column chromatography (n-hexane: EtOAc ¼ 5: 1, EtOAc) was carried out using the
37. 4- (3-Methoxyphenyl) -3- (4-methoxyphenyl) isoquinolin-1 (2H)
Compound 14f (2.16 g) and AcOH: H 2 O ¼ 9: 1 (20 mL) were subjected to the procedure of the
38. 3-Aryl-4- (3-methoxyphenyl) isoquinolin-1 (2H)
(N-hexane: EtOAc ¼ 3: 1, EtOAc) was carried out by using 14 g (1.83 g, 3.84 mmol) of the
39. 1-Chloro-4- (3-methoxyphenyl) -6-methyl-3- (o- tolyl) isoquinoline (7a)
Column chromatography (n-hexane:
40. 1-Chloro-3- (3,4-dimethoxyphenyl) -4- (3-methoxyphenyl) -6-methylisoquinoline (7b)
41. 1-Chloro-4- (3-methoxyphenyl) -6-methyl-3- (m- tolyl) isoquinoline (7c)
Column chromatography (n-hexane: EtOAc ¼ 5: 1, 4: 1) was performed using
42. 1-Chloro-3- (2,6-dimethylphenyl) -4- (3-methoxyphenyl) -6-methylisoquinoline (7d)
The
43. 1-Chloro-3- (2-methoxyphenyl) -4- (3-methoxyphenyl) isoquinoline (7e)
44. 1-Chloro-4- (3-methoxyphenyl) -3- (4-methoxyphenyl) isoquinoline (7f)
45. 3-Aryl-1-chloro-4- (3-methoxyphenyl) isoquinoline (7 g)
Column chromatography (n-hexane:
46. 1- (4-Ethylpiperazin-1-yl) -4- (3-methoxyphenyl) -6-methyl- 3- (o- tolyl) isoquinoline (6ac)
It was dissolved in 1-ethyl piperazine (324 mg, 2.83 mmol) and K 2 CO 3 (882 mg, 6.38 mmol) was added to the former, compound 7a (265 mg, 0.71 mmol) to DMF (5 mL). The reaction mixture was heated to 150 < 0 > C in an oil bath. After completion of the reaction, water (50 mL) was added, followed by extraction with ethanol. The organic layer was washed with water, dried with brine and anhydrous Na2CO3, and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: EtOAc ¼ 5: 1, 3: 1, EtOAc, MeOH) to give the brown semi solid compound 6ac (288 mg, 90%). 1H, Ar-H), 7.35-7.31 (m, 1H, Ar-H), 8.06 (d, J = (M, 2H, Ar-H), 7.19-7.04 (m, 3H, Ar-H), 6.97-6.90 2H), 3.65 (s, 3H, OCH3), 3.53 (m, 4H, 100-N (CH2) , 2.41 (s, 3H, Ar-CH3), 2.18 (s, 3H, Ar-CH3), 1.17 (t, J = 7.2 Hz, 3H, CH2CH3). 129.6, 128.9, 128.9, 128.4, 127.5, 126.9, 125.2, 125.0, 124.6, 123.7 (ddp): 158.9, 149.5, 139.6, 139.0, 138.1, 136.4, , 118.3, 116.5, 112.5, 55.0, 52.9, 52.5, 51.2, 22.0, 20.2, 11.9. MS (ESI): m / z 452 (M + H) < + >.
47. 2- (4- (4- (3- Methoxyphenyl ) -6- methyl -3- (o- Tolyl ) Isoquinolin-1-yl) piperazin-l-yl) - N, N - Dimethylethanamine (6ad)
Compound 7a (220 mg, 0.58 mmol), 1- [2- (dimethylamino) ethyl] piperazine (370 mg, 2.35 mmol), K 2 CO 3 (732 mg, 5.29 mmol) DMF (5 mL) was used and column chromatography (nhexane:
48. 4- (3-Methoxyphenyl) -6-methyl-N- (4-methylpiperazin- 1 -yl) -3- (o- tolyl) isoquinolin-
Amino-4-methylpiperazine (244 mg, 2.05 mmol), K 2 CO 3 (639 mg, 4.62 mmol) and DMF (7 mL) were added to a solution of Compound 7a (192 mg, 0.51 mmol) mL) and column chromatography (n-hexane:
49. N- (1-Ethylpiperidin-4-yl) -4- (3- methoxyphenyl) -6-methyl- 3- (o- tolyl) isoquinolin-
(271 mg, 0.72 mmol), 97% 3-amino-N-ethylpiperidine (383 mg, 2.89 mmol), K 2 CO 3 (902 mg, 6.52 mmol) and DMF (7 mL), and column chromatography (nhexane:
50. N- (4-Methoxybenzyl) -4- (3-methoxyphenyl) -6-methyl-3- (o- tolyl) isoquinolin-
The compound 7a (314 mg, 0.84 mmol), 98% 4-methoxybenzylamine (461 mg, 3.36 mmol), K 2 CO 3 (N-hexane:
51. N-Benzyl-4- (3-methoxyphenyl) -6-methyl-3- (o-tolyl) isoquinolin-
Compound 7a (110 mg, 0.29 mmol), benzylamine (126 mg, 1.17 mmol), K 2 CO 3 (366 mg, 2.64 mmol) and DMF (5 mL), and column chromatography (n-hexane, CH 2 Cl 2 ) was carried out to obtain a yellow semi-solid compound, 6an (43 mg, 32%). Mp: 127-129 占 폚. (D, J = 8.4 Hz, 1H, Ar-H), 8.05 (t, J = 6.0 Hz, 1H, NH), 7.39-7.23 2H, Ar-H), 7.21-7.12 (m, 3H, Ar-H), 7.01-6.99 2H, Ar-H), 6.56 (s, 3H, Ar-H), 4.69 s, 3H, Ar-CH3). 13C NMR (125 MHz, CDCl3) d (ppm): 158.9, 153.2, 150.1, 141.4, 140.0, 139.7, 139.4, 137.2, 136.3, 130.2, 129.5, 128.5, 128.0, 127.4, 127.1, 126.8, 125.3, 124.6, , 121.1, 114.8, 112.2, 55.0, 45.8, 21.9, 20.1. MS (ESI): m / z 445 (M + H) < + >. Anal. calcd for C31H28N2O 0.35C4H8O2: C, 81.86; H, 6.53; N, 5.89. Found C, 81.78; H, 6.31; N, 5.88.
52. 3- (3,4-Dimethoxyphenyl) -4- (3-methoxyphenyl) -6-methyl- 1- (piperazin- 1 -yl) isoquinoline (6ba)
The compound 7b (300 mg, 0.71 mmol), anhydrous piperazine (246 mg, 2.85 mmol), K 2 CO 3 (889 mg, 6.43 mmol) and DMF (7 mL) Chromatography (n-hexane: EtOAc ¼ 5: 1, 3: 1, EtOAc, MeOH) gave the clear semi-solid compound 6ba (283 mg, 84%). Rf 0.11 (MeOH). Mp: 82-85 C. IR (cm-1): 3411 (NH). (D, J = 8.4, 1H, Ar-H), 7.39-7.31 (m, 3H, Ar-H), 7.16 (M, 2H, Ar-H), 6.95-6.92 (m, 1H, Ar-H), 6.89 (d, J = 2.1 Hz, 3H, OCH3), 3.51 (s, 3H, OCH3), 3.46-3.43 (d, J = 2.7, 1.5 Hz, 1H, Ar-H) (m, 4H, 100-N (CH2) 2), 3.15-3.12 (m, 4H, 400-N (CH2) 2), 2.38 (s, 3H, 6-CH3). 129.9, 128.3, 125.36, 125.31, 124.3, 123.9, 122.8, 117.8, 116.8, 113.4 (ddp): 159.7, 158.4, 148.0, 147.4, 146.7, 140.1, 139.7, 138.8, 133.2, , 112.7, 110.3, 55.7, 55.4, 55.2, 48.7, 43.4, 22.0. MS (ESI): m / z 470 (M + H) < + >. HRMS (ESI): m / z 470.2442 (M + H) + calcd for C29H32N3O3, 470.2444, 492.2260 (M + Na) + (calcd for C29H31N3NaO3, 492.2263).
53. 3- (3,4-Dimethoxyphenyl) -4- (3-methoxyphenyl) -6-methyl- 1- (4-methylpiperazin- 1 -yl) isoquinoline (6bb)
Compound 7b (200 mg, 0.47 mmol), 1-methylpiperazine (191 mg, 1.9 mmol), K 2 CO 3 (592 mg, 4.28 mmol) and DMF , Followed by column chromatography (n-hexane:
54. 3- (3,4- Dimethoxyphenyl ) -4- (3- Methoxyphenyl ) -6- methyl -N- (3- (2- Methylpiperazine -1-yl) propyl) isoquinolin-1-amine (6bk)
(356 mg, 0.84 mmol), 96% 1- (3-aminopropyl) -2-piperazine (552 mg, 3.39 mmol) and K 2 CO 3 (1.05 g, 7.63 mmol) (424 mg, 92%) was obtained as a yellow semisolid compound by performing column chromatography (nhexane: EtOAc ¼ 3: 1, EtOAc,
55. 3- (3,4-Dimethoxyphenyl) -N- (4-methoxybenzyl) -4- (3-methoxyphenyl) -6-methylisoquinolin-
(350 mg, 0.83 mmol), 98% 4-methoxybenzylamine (467 mg, 3.33 mmol), K 2 CO 3 (1.03 g, 7.50 mmol) and DMF (5 mL) , And column chromatography (n-hexane: EtOAc ¼ 5: 1, 3: 1) was performed to obtain 6bm of a green solid compound (289 mg, 66%). Rf 0.17 (n-hexane:
56. 1- (4-Ethylpiperazin-1-yl) -4- (3-methoxyphenyl) -6-
3- (m-tolyl) isoquinoline (6cc)
Compound 7c (200 mg, 0.53 mmol), 1-ethylpiperazine (244 mg, 2.139 mmol), K 2 CO 3 (665 mg, 4.81 mmol) and DMF (5 mL) , Followed by column chromatography (n-hexane:
57. N- (3-Methoxyphenyl) -4- (3-methoxyphenyl) -6-methyl-3- (m- tolyl) isoquinolin-
The compound 6c was treated with Compound 7c (200 mg, 0.53 mmol), 2- (3-methoxyphenyl) ethylamine (324 mg, 2.14 mmol), K 2 CO 3 (665 mg, 4.81 mmol) (238 mg, 91%) was obtained by carrying out column chromatography (nhexane:
58. 4- (3-Methoxyphenyl) -6-methyl-N-phenyl-3- (m-tolyl) isoquinolin-
The compound 6c was treated with Compound 7c (211 mg, 0.56 mmol), aniline (210 mg, 2.25 mmol), K 2 CO 3 (702 mg, 5.08 mmol) and DMF (5 mL) (114 mg, 46%) was obtained by carrying out the procedure described for the synthesis of the title compound in a manner similar to that described in Example 1, but using n-hexane:
59. 3- (2,6-Dimethylphenyl) -4- (3-methoxyphenyl) -6-methyl- 1- (piperazin- 1 -yl) isoquinoline (6da)
Compound 7d (200 mg, 0.51 mmol), anhydrous piperazine (177 mg, 2.06 mmol), K 2 CO 3 (641 mg, 4.64 mmol) and DMF (7 mL) Chromatography (n-hexane:
60. 3- (2,6-Dimethylphenyl) -N- (4-methoxybenzyl) -4- (3-methoxyphenyl) -6-methylisoquinolin-
Compound 7d (400 mg, 1.03 mmol), 98% 4-methoxybenzylamine (577 mg, 4.12 mmol), K 2 CO 3 (1.28 g, 9.28 mmol) and DMF (7 mL) And subjected to column chromatography (CH2Cl2, nhexane:
61. 3- (2-Methoxyphenyl) -4- (3-methoxyphenyl) -1- (piperazin-1-yl) isoquinoline (6ea)
The compound 7e (200 mg, 0.53 mmol), anhydrous piperazine (183 mg, 2.12 mmol), K 2 CO 3 (662 mg, 4.79 mmol) and DMF (7 mL) (N-hexane: EtOAc ¼ 4: 1, EtOAc, MeOH) to give the clear semi-solid compound 6ea (184 mg, 81%). Rf 0.16 (MeOH). IR (cm < -1 >): 3454 (NH). H-NMR (300 MHz, CD30D) d (ppm): 8.26-8.21 (m, 1H, Ar-H), 7.58-7.54 3H, OCH3), 3.42-3.38 (m, 4H, Ar-H), 6.87-6.74 (m, 4H, 100-N (CH2) 2), 3.13-3.09 (M, 4H, 400-N (CH2) 2). (Ppm): 159.2, 158.7, 156.3, 146.5, 138.8, 137.7, 131.5, 130.6, 129.6, 128.7, 128.4, 127.6, 126.2, 125.8, 124.8, 123.7, 120.1, 120.0, 116.1 , 112.7, 110.6, 55.08, 55.0, 50.1, 44.1. MS (ESI): m / z 426 (M + H) < + >.
62. 2- (4- (3- (2- Methoxyphenyl ) -4- (3- Methoxyphenyl ) Isoquinolin-1-yl) piperazin-l-yl) - N, N - Dimethylethanamine (6Ed)
(332 mg, 2.12 mmol), K 2 CO 3 (662 mg, 4.79 mmol) and DMF ( 2 mL) were added to a solution of compound 7e (200 mg, 0.53 mmol), 1- [2- (dimethylamino) ethyl] piperazine (5 mL), and column chromatography (nhexane:
63. 3- (2-Methoxyphenyl) -4- (3-methoxyphenyl) -1- (4- (2- methoxyphenyl) piperazin- 1 -yl) isoquinoline (6ee)
The compound 7e (200 mg, 0.53 mmol), 1- (2-methoxyphenyl) piperazine (409 mg, 2.12 mmol), K 2 CO 3 (662 mg, 4.79 mmol) and
64. 3- (2-Methoxyphenyl) -4- (3-methoxyphenyl) -1- (4- (pyrimidin- 2- yl) piperazin- 1- yl) isoquinoline (6ef)
The compound 7e (200 mg, 0.53 mmol), 1- (2-pyrimidyl) piperazine (349 mg, 2.12 mmol), K 2 CO 3 (662 mg, 4.79 mmol) and DMF mL) and column chromatography (n-hexane: EtOAc ¼ 5: 1, 3: 1) gave the compound 6ef as a yellow solid (219 mg, 81%). Rf 0.24 (n-hexane:
65. 1- (1H-Imidazol-1-yl) -3- (2-methoxyphenyl) -4- (3-methoxyphenyl) isoquinoline
The compound 7e (110 mg, 0.29 mmol), imidazole (29 mg, 0.44 mmol), K 2 CO 3 (23 mg, 0.58 mmol) and DMF (5 mL) (67 mg, 56%) was obtained as an off-white solid by following the procedure as outlined in Example 1b (n-hexane: EtOAc ¼ 5: 1, 1: 1, EtOAc). Rf 0.45 (EtOAc). 1H), 7.84 (d, J = 8.0 Hz, 1H, Ar-H) H, Ar-H), 7.71-7.60 (m, 3H, Ar-H), 7.30-7.21 (m, z5H, Ar-H, partially overlapped with the CHCl3 peak), 6.92-6.82 (m, 3H, Ar-H), 6.80-6.72 (m, 1H, Ar-H), 3.67 (s, 3H, OCH3), 3.53 (s, 3H, OCH3). 129.9, 129.3, 130.9, 129.4, 129.1, 128.5, 127.9, 126.3, 124.2, 123.2, 121.7, 120.2, 115.9, 113.3 , 110.6, 55.1, 54.9. MS (ESI): m / z 408 (M + H) < + >, 449 (M + CH3CN + H) < + >. Anal. Calcd for C26H21N3O2 $ 0.35C4H8O2: C, 75.08; H, 5.47; N, 9.59. Found C, 74.62; H, 5.09; N, 10.05.
66. 3- (2-Methoxyphenyl) -4- (3-methoxyphenyl) -N- (4-methylpiperazin- 1 -yl) isoquinolin-
Amino-4-methylpiperazine (253 mg, 2.12 mmol), K 2 CO 3 (662 mg, 4.79 mmol) and DMF (5 mg) were added to a solution of compound 7e (200 mg, 0.53 mmol) mL) and column chromatography (n-hexane: EtOAc ¼ 5: 1, EtOAc, MeOH) gave the orange semi solid compound 6ei (143 mg, 58%). Rf 0.5 0.5 (MeOH). IR (cm < -1 >): 3451 (NH). 1H, Ar-H), 7.54-7.45 (m, 2H, Ar-H), 7.71-7.67 (m, ), 7.27-7.13 (m, z1H, Ar-H, partially overlapped with the CHCl3 peak), 7.21-7.13 (m, 2H, Ar-H), 6.89 (td, J = 7.5, 1.2 Hz, (S, 3H, OCH3), 3.60-3.56 (m, 4H, N (CH3) 2), 3.46 -2.76 (m, 4H, N (CH2) 2), 2.45 (s, 3H, NCH3). (Ppm): 159.7, 158.7, 156.3, 146.5, 139.1, 137.6, 131.6, 130.9, 129.3, 128.6, 128.1, 126.8, 126.0, 125.3, 125.2, 123.7, 120.2, 120.0, 116.1 , 112.6, 110.7, 55.0, 50.8, 45.9. MS (ESI): m / z 408 (M + H-15) < + >.
67. N- (4-Methoxybenzyl) -3- (2-methoxyphenyl) -4- (3- methoxyphenyl) isoquinolin-
The compound 7e (310 mg, 0.82 mmol), 98% 4-methoxybenzylamine (462 mg, 3.29 mmol), K 2 CO 3 (1.02 g, 7.42 mmol) and DMF (5 mL) , And MPLC (n-hexane:
68. 1- (4-Ethylpiperazin-1-yl) -4- (3-methoxyphenyl) -3- (4-methoxyphenyl) isoquinoline (6fc)
The compound 7f (211 mg, 0.56 mmol), 1-ethylpiperazine (256 mg, 2.24 mmol), K 2 CO 3 (698 mg, 5.05 mmol) and DMF (5 mL) Column chromatography (n-hexane:
69. 2- (4- (4- (3- Methoxyphenyl ) -3- (4- Methoxyphenyl ) Isoquinolin-1-yl) piperazin-l-yl) - N, N - Dimethylethanamine (6fd)
The compound 7f (210 mg, 0.55 mmol), 1- [2- (dimethylamino) ethyl] piperazine (351 mg, 2.23 mmol), K 2 CO 3 (695 mg, 5.02 mmol) (5 mL) and column chromatography (n-hexane:
70. Synthesis of 4- (3-methoxyphenyl) -3- (4-methoxyphenyl) -30,40-dihydro-10H-1,20-bisisoquinoline (6fg)
The compound 7f (213 mg, 0.56 mmol), 1,2,3,4-tetrahydroisoquinoline (302 mg, 2.26 mmol), K 2 CO 3 (705 mg, 5.1 mmol) (5 mL) and column chromatography (nhexane:
71. N- (4-Methoxybenzyl) -4- (3-methoxyphenyl) -3- (4-methoxyphenyl) isoquinolin- 1 -amine (6fm)
(463 mg, 3.33 mmol), K 2 CO 3 (1.03 g, 7.49 mmol) and DMF (5 mL) were added to a solution of Compound 7f (313 mg, 0.83 mmol), 98% , And column chromatography (nhexane: CH2Cl2 ¼ 1: 1, n-hexane: EtOAc ¼ 5: 1) was carried out to obtain a white solid compound 6fm (281 mg, 75%). Rf 0.24 (nhexane:
72. 3-Aryl-4- (3-methoxyphenyl) -1- (piperazin-1-yl) isoquinoline (6ga)
7 g (200 mg, 0.41 mmol), anhydrous piperazine (143 mg, 1.66 mmol), K 2 CO 3 (516 mg, 3.37 mmol) and DMF (7 mL) Column chromatography (n-hexane: EtOAc ¼ 5: 1, EtOAc, MeOH) gave the off-white solid compound 6ga (103 mg, 46%). Rf 0.17 (MeOH). Mp: 99-102 [deg.] C. IR (cm < -1 >): 3451 (NH). 1H), 7.65-7.59 (m, 2H, Ar-H), 7.51-7.46 (m, J, 7.5 Hz, 1H, Ar-H), 7.29 (t, J = 8.0 Hz, (D, J = 9.0, 2.0 Hz, 1H, Ar-H), 7.01 (s, 3H, OCH3), 3.52 (s, 4H, 100-N (CH2) 2), 3.25 (s, 4H, 400-N (CH2) 2), 2.96 (s, 3H, OCH3). 130.9, 129.7, 129.55, 129.51, 128.4, 127.8, 127.3, 126.3, 125.9, 125.4 (ppm): 159.8, 158.9, 156.2, 146.3, 142.3, 138.8, 137.7, 132.8, , 124.7, 123.7, 120.1, 119.2, 116.2, 112.9, 112.3, 111.9, 111.0, 55.2, 55.0, 49.5, 43.7. HRMS (ESI): m / z 532.2600 (M + H) + calcd for C34H34N3O3, 532.2600, 554.2417 (M + Na) + (calcd for C34H33N3NaO3, 554.2420).
73. 3-Aryl-4- (3-methoxyphenyl) -1- (4-methylpiperazin-1-yl) isoquinoline (6gb)
7 g (200 mg, 0.41 mmol), 1-methylpiperazine (166 mg, 1.66 mmol), K 2 CO 3 (516 mg, 3.73 mmol) and DMF , Followed by column chromatography (n-hexane: EtOAc ¼ 5: 1, EtOAc, MeOH) to give 6 gb of a brown semisolid compound (180 mg, 79%). Rf 0.58 (MeOH). (M, 2H, Ar-H), 7.44 (dd, J = 8.5, 2.4 Hz, 1H), 7.63-7.56 (M, 1H, Ar-H), 7.37 (d, J = 2.3 Hz, 1H, Ar-H), 7.28-7.17 3H, OCH3), 3.59 (s, 3H, OCH3), 3.83 (s, 3H, OCH3) ), 3.53 (s, 4H, 100-N (CH2) 2), 2.87 (t, J4.4 Hz, 4H, 400-N (CH2) 2), 2.48 (s, 3H, NCH3). 129.9, 130.6, 129.53, 129.5, 128.3, 127.2, 127.1, 126.1, 125.5, 125.1 (ppm): 159.8, 159.6, 158.8, 156.2, 146.3, 142.4, 139.0, 137.6, , 123.8, 120.2, 119.2, 116.2, 112.8, 112.3, 111.9, 111.1, 55.3, 55.2, 55.0, 54.5, 50.3, 45.3.
74. 3-Aryl-4- (3-methoxyphenyl) -1- (4- (pyrimidin-2- yl) piperazin- 1- yl) isoquinoline (6gf)
(200 mg, 0.41 mmol), 1- (2-pyrimidyl) piperazine (272 mg, 1.66 mmol), K 2 CO 3 (516 mg, 3.73 mmol) and DMF mL) was applied followed by column chromatography (n-hexane: EtOAc ¼ 5: 1) to give 6 gf of a transparent semi-solid compound (184 mg, 72%). Rf 0.6 (nhexane:
75. 3-Aryl-N- (4-methoxybenzyl) -4- (3-methoxyphenyl) isoquinolin- 1 -amine (6 gm)
To a solution of 7g (300 mg, 0.62 mmol), 98% 4-methoxybenzylamine (348 mg, 2.49 mmol), K 2 CO 3 (774 mg, 5.6 mmol) and DMF (5 mL) Followed by column chromatography (nhexane:
76. 4- (3-Methoxyphenyl) -6-methyl-3- (o-tolyl) isoquinolin- 1 -amine (17a)
Compound 6am (358 mg, 0.75 mmol) was dissolved in CH 2 Cl 2 (15 mL) and then trifluoroacetic acid (4 mL) was added. The reaction mixture was refluxed for 19 hours. An excess of trifluoroacetic acid was neutralized with saturated NaHCO 3 solution (100 mL) and extracted with CH 2 Cl 2 . The organic layer was washed with water and concentrated under reduced pressure. The residue was subjected to column chromatography (nhexane: EtOAc ¼ 4: 1, 1: 1) to give an off-white
77. 3- (3,4-Dimethoxyphenyl) -4- (3-methoxyphenyl) -6-methylisoquinolin- 1 -amine (17b)
Compound 6bm (273 mg, 0.52 mmol), trifluoroacetic acid (5 mL), and CH 2 Cl 2 (10 mL) were applied to the
78. 3- (2,6-Dimethylphenyl) -4- (3-methoxyphenyl) -6-methylisoquinolin- 1 -amine (17c)
Compound 6dm (263 mg, 0.53 mmol), trifluoroacetic acid (5 mL), and CH 2 Cl 2 (10 mL) were applied to the procedure of
79. 3- (2-Methoxyphenyl) -4- (3-methoxyphenyl) isoquinolin- 1 -amine (17d)
Compound 6em (200 mg, 0.42 mmol), trifluoroacetic acid (5 mL), and CH 2 Cl 2 (10 mL) were applied to the procedure of
80. 4- (3-Methoxyphenyl) -3- (4-methoxyphenyl) isoquinolin- 1 -amine (17e)
Compound 6fm (239 mg, 0.53 mmol), trifluoroacetic acid (5 mL), and CH 2 Cl 2 (15 mL) were applied to the procedure of
81. 3- (3- (1-Methoxy-6-methyl-3- (o-tolyl) isoquinolin-
To a solution of compound 14a '(611 mg, 1.72 mmol) in DMF (15 mL) was added potassium carbonate (713 mg, 5.15 mmol) followed by 96% 3- (dimethylamino) propyl chloride HCl mmol). The reaction mixture was heated to 130 < 0 > C in an oil bath. To the reaction mixture was added water (100 mL) and extracted with EtOAc. The organic layer was washed with water and concentrated under reduced pressure. The residue was purified by column chromatography (nhexane: EtOAc ¼ 5: 1, 3: 1, EtOAc, MeOH) to give an egg yolk color semi-solid compound 18 (542 mg, 71%). (M, 3H, ArH), 7.39-7.36 (m, 2H, Ar-H), 7.17-7.05 (m, 3H, 3H, OCH3), 3.94-3.76 (m, 2H, OCH2), 7.02-6.94 (m, 2H, Ar-H), 6.77-6.66 , 2.42-2.36 (m, 5H, Ar-CH3, CH2 (NCH3) 2), 2.23 (s, 6H, N (CH3) 6.9 Hz, 2H,
82. 4- (3- (3- (Dimethylamino) propoxy) phenyl) -6-methyl-3- (o-tolyl) isoquinolin-
Compound 18 (466 mg, 1.05 mmol) and AcOH: H2O ¼ 9: 1 (10 mL) were applied to the procedure of
Cytotoxicity experiment
In the present invention, four cell lines were used: MCF-10A, T47D, DU145, and HCT-15. Cells were plated at 2-4 x 10 4 / well in 96-well plates and cultured for one day under culture medium supplemented with 10% fetal bovine serum. On
Topoisomerase inhibition
The topo I inhibitory activity of the compounds was determined by measuring the release of supercoiled plasmid DNA, pBR322. A mixture of pBR322 (100 ng) and recombinant human DNA topo I (0.4 units; Topo-GEN INC., USA) was diluted in a relaxation buffer (10 mM TriseHCl pH 7.9, 150 mM NaCl, 0.1% bovine serum albumin, 1 mM spperidine, 5% glycerol) at 37 ° C for 30 minutes. To a final reaction volume of 10 mL was added 2.5 mL stop solution containing 5% sarcosyl, 0.0025% bromophenol blue and 25% glycerol. Then, the DNA sample was electrophoresed on 1% agarose gel and stained with ethidium bromide (0.5 mg / mL) for 30 minutes. The DNA band was observed by transmitting UV, and supercoiled DNA was quantified with AlphaImager (Alpha Innotech Corporation).
The topo IIa inhibitory activity of the compounds was determined as follows. 50 mM KCl, 5
Molecular docking
Docking studies were performed using the Surflex Dock program in Sybyl-X 2.0 (winnt_os5x). The structure of DNA-topo I-topotecan was downloaded from the Protein Data Bank (PDB: 1K4T). Hg atoms, polyethylene glycol (PEG) and topotecan open carboxylate forms were removed. The topotecan was extracted. Minimization was performed by adding hydrogen and using the MMFF94s force field of MMFF94 charges and using the conjugate gradient method, distance-dependent dielectric constant and converging to 0.01 kcal / mol · Å. The -SH group of the scissile DNA strand G11 nucleotide was converted to -OH. Protomol is an optimized representative ligand that forms all of the interactions with binding sites, which are generated based on the ligand mode. Diarylisoquinoline and topotecan were constructed in Sybyl; The energy was minimized as MMFF94s force field and MMFF94 charges and stored in the Sybyl database. The compound in the Sybyl database was docked to the binding site of the Surflex Dock based on the previously constructed protomole. The extracted topotecan was used as a reference molecule. The docking proto can reproduce the position of the topotecan (manually constructed and stored in the Sybyl database) at the binding site where the mean square root deviation (rmsd) of the extracted topotecan heavy atoms is 0.61 Å. Similarly, the structure of DNA-topo Ⅱ beta -etoposide was downloaded from the Protein Data Bank (PDB: 3QX3). topo & lt ; RTI ID = 0.0 > II < / RTI > monomers, etoposide molecules and 3 Mg2 + interacting with the monomers. Gln778 and Ala816 were modified to Met and Ser, respectively, in the remaining monomers. The binding length, coupling angle, and torsional angle of the modified side chains were adjusted to match Met762 and Ser800 of DNA-topo IIα (PDB: 4FM9). The rest of the procedure was performed using a method similar to that described in topo I. The docking proto can reproduce the position of the passively constructed etoposide at the binding site with the middle atom of 0.54 Armsd of the extracted etoposide.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
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Claims (12)
4- (3-methoxyphenyl) -6-methyl-3- (o-tolyl) isoquinolin-1 (2H) -one (5a);
3- (3,4-dimethoxyphenyl) -4- (3-methoxyphenyl) -6-methylisoquinolin-1 (2H) -one (5b);
4- (3-Methoxyphenyl) -6-methyl-3- (m-tolyl) isoquinolin-1 (2H) -one (5c);
3- (2-methoxyphenyl) -4- (3-methoxyphenyl) isoquinolin-1 (2H) -one (5e);
4- (3-methoxyphenyl) -3- (4-methoxyphenyl) isoquinolin-1 (2H) -one (5f);
4- (3- (3- (dimethylamino) propoxy) phenyl) -6-methyl-3- (o-tolyl) isoquinolin-1 (2H) -one (19);
1- (4-Ethylpiperazin-1-yl) -4- (3-methoxyphenyl) -6-methyl-3- (o-tolyl) isoquinoline (6ac);
Yl) piperazin-1-yl) -N, N-dimethylethanamine (prepared from 2- (4- (4- (3-methoxyphenyl) -6- 6ad);
N- (4-methoxybenzyl) -4- (3-methoxyphenyl) -6-methyl-3- (o-tolyl) isoquinolin-1 -amine (6am);
3- (3,4-dimethoxyphenyl) -4- (3-methoxyphenyl) -6-methyl-1- (4-methylpiperazin-1-yl) isoquinoline (6bb);
3- (3,4-Dimethoxyphenyl) -N- (4-methoxybenzyl) -4- (3-methoxyphenyl) -6-methylisoquinolin-1 -amine (6bm);
4- (3-methoxyphenyl) -6-methyl-N-phenyl-3- (m-tolyl) isoquinolin-1 -amine (6co);
3- (2,6-Dimethylphenyl) -N- (4-methoxybenzyl) -4- (3-methoxyphenyl) -6-methylisoquinolin-1 -amine (6dm);
3- (2-methoxyphenyl) -4- (3-methoxyphenyl) -1- (piperazin-1-yl) isoquinoline (6ea);
1-yl) -N, N-dimethylethanamine (6eI) in the presence of a base, such as 2- (4- (3- (2- ;
3- (2-methoxyphenyl) -4- (3-methoxyphenyl) -1- (4- (2-methoxyphenyl) piperazin-1-yl) isoquinoline (6ee);
3- (2-methoxyphenyl) -4- (3-methoxyphenyl) -1- (4- (pyrimidin-2-yl) piperazin-1-yl) isoquinoline (6ef);
1- (1H-imidazol-1-yl) -3- (2-methoxyphenyl) -4- (3-methoxyphenyl) isoquinoline (6eI);
3- (2-methoxyphenyl) -4- (3-methoxyphenyl) -N- (4-methylpiperazin-1-yl) isoquinolin-1 -amine (6ei);
N- (4-methoxybenzyl) -3- (2-methoxyphenyl) -4- (3-methoxyphenyl) isoquinolin-1 -amine (6em);
1- (4-ethylpiperazin-1-yl) -4- (3-methoxyphenyl) -3- (4-methoxyphenyl) isoquinoline (6fc);
1-yl) -N, N-dimethylethanamine (6fd) was obtained in the same manner as in Example 1, except that 2- (4- (4- (4- (3- methoxyphenyl) -3- ;
4- (3-methoxyphenyl) -3- (4-methoxyphenyl) -30,40-dihydro-10H-1,20-nonisoquinoline (6fg);
N- (4-methoxybenzyl) -4- (3-methoxyphenyl) -3- (4-methoxyphenyl) isoquinolin-1 -amine (6fm);
3-aryl-4- (3-methoxyphenyl) -1- (4-methylpiperazin-1-yl) isoquinoline (6gb);
3-aryl-4- (3-methoxyphenyl) -1- (4- (pyrimidin-2-yl) piperazin-1-yl) isoquinoline (6 gf); or
4- (3-Methoxyphenyl) -3- (4-methoxyphenyl) isoquinolin-1 -amine (17e).
3- (3,4-dimethoxyphenyl) -4- (3-methoxyphenyl) -6-methylisoquinolin-1 (2H) -one (5b);
4- (3-Methoxyphenyl) -6-methyl-3- (m-tolyl) isoquinolin-1 (2H) -one (5c);
3- (2-methoxyphenyl) -4- (3-methoxyphenyl) isoquinolin-1 (2H) -one (5e);
4- (3- (3- (dimethylamino) propoxy) phenyl) -6-methyl-3- (o-tolyl) isoquinolin-1 (2H) -one (19);
Yl) piperazin-1-yl) -N, N-dimethylethanamine (prepared from 2- (4- (4- (3-methoxyphenyl) -6- 6ad);
3- (3,4-dimethoxyphenyl) -4- (3-methoxyphenyl) -6-methyl-1- (piperazin-1-yl) isoquinoline (6ba);
3- (3,4-dimethoxyphenyl) -4- (3-methoxyphenyl) -6-methyl-1- (4-methylpiperazin-1-yl) isoquinoline (6bb);
(3-methoxyphenyl) -6-methyl-N- (3- (2-methylpiperidin- 1 -yl) propyl) isoquinoline- Amine (6bk);
1- (4-Ethylpiperazin-1-yl) -4- (3-methoxyphenyl) -6-methyl-3- (m-tolyl) isoquinoline (6cc);
3- (2-methoxyphenyl) -4- (3-methoxyphenyl) -1- (piperazin-1-yl) isoquinoline (6ea);
1-yl) -N, N-dimethylethanamine (6eI) in the presence of a base, such as 2- (4- (3- (2- ;
1- (4-ethylpiperazin-1-yl) -4- (3-methoxyphenyl) -3- (4-methoxyphenyl) isoquinoline (6fc);
3- (3,4-dimethoxyphenyl) -4- (3-methoxyphenyl) -6-methylisoquinolin-1 -amine (17b);
3- (2,6-dimethylphenyl) -4- (3-methoxyphenyl) -6-methylisoquinolin-1 -amine (17c); or
3- (2-Methoxyphenyl) -4- (3-methoxyphenyl) isoquinolin-1 -amine (17d).
3- (3,4-dimethoxyphenyl) -4- (3-methoxyphenyl) -6-methylisoquinolin-1 (2H) -one (5b);
4- (3-Methoxyphenyl) -6-methyl-3- (m-tolyl) isoquinolin-1 (2H) -one (5c);
3- (2,6-dimethylphenyl) -4- (3-methoxyphenyl) -6-methylisoquinolin-1 (2H) -one (5d);
3- (2-methoxyphenyl) -4- (3-methoxyphenyl) isoquinolin-1 (2H) -one (5e);
4- (3-methoxyphenyl) -3- (4-methoxyphenyl) isoquinolin-1 (2H) -one (5f);
3-aryl-4- (3-methoxyphenyl) isoquinolin-1 (2H) -one (5 g);
1- (4-Ethylpiperazin-1-yl) -4- (3-methoxyphenyl) -6-methyl-3- (o-tolyl) isoquinoline (6ac);
Yl) piperazin-1-yl) -N, N-dimethylethanamine (prepared from 2- (4- (4- (3-methoxyphenyl) -6- 6ad);
4- (3-methoxyphenyl) -6-methyl-N- (4-methylpiperazin-1-yl) -3- (o-tolyl) isoquinolin-1 -amine (6ai);
N- (1-Ethylpiperidin-4-yl) -4- (3-methoxyphenyl) -6-methyl-3- (o-tolyl) isoquinolin-1 -amine (6aj);
N- (4-methoxybenzyl) -4- (3-methoxyphenyl) -6-methyl-3- (o-tolyl) isoquinolin-1 -amine (6am);
3- (3,4-dimethoxyphenyl) -4- (3-methoxyphenyl) -6-methyl-1- (piperazin-1-yl) isoquinoline (6ba);
3- (3,4-dimethoxyphenyl) -4- (3-methoxyphenyl) -6-methyl-1- (4-methylpiperazin-1-yl) isoquinoline (6bb);
(3-methoxyphenyl) -6-methyl-N- (3- (2-methylpiperidin- 1 -yl) propyl) isoquinoline- Amine (6bk);
1- (4-Ethylpiperazin-1-yl) -4- (3-methoxyphenyl) -6-methyl-3- (m-tolyl) isoquinoline (6cc);
(6-methyl-3- (m-tolyl) isoquinolin-1-amine (6-methoxyphenyl)
4- (3-methoxyphenyl) -6-methyl-N-phenyl-3- (m-tolyl) isoquinolin-1 -amine (6co);
3- (2,6-dimethylphenyl) -4- (3-methoxyphenyl) -6-methyl-1- (piperazin-1-yl) isoquinoline (6da);
1- (1H-imidazol-1-yl) -3- (2-methoxyphenyl) -4- (3-methoxyphenyl) isoquinoline (6eI);
3- (2-methoxyphenyl) -4- (3-methoxyphenyl) -N- (4-methylpiperazin-1-yl) isoquinolin-1 -amine (6ei);
1- (4-ethylpiperazin-1-yl) -4- (3-methoxyphenyl) -3- (4-methoxyphenyl) isoquinoline (6fc);
1-yl) -N, N-dimethylethanamine (6fd) was obtained in the same manner as in Example 1, except that 2- (4- (4- (4- (3- methoxyphenyl) -3- ;
4- (3-methoxyphenyl) -3- (4-methoxyphenyl) -30,40-dihydro-10H-1,20-nonisoquinoline (6fg);
N- (4-methoxybenzyl) -4- (3-methoxyphenyl) -3- (4-methoxyphenyl) isoquinolin-1 -amine (6fm);
3-aryl-4- (3-methoxyphenyl) -1- (4-methylpiperazin-1-yl) isoquinoline (6gb);
3-aryl-N- (4-methoxybenzyl) -4- (3-methoxyphenyl) isoquinolin-1 -amine (6 gm);
4- (3-methoxyphenyl) -6-methyl-3- (o-tolyl) isoquinolin-1 -amine (17a);
3- (3,4-dimethoxyphenyl) -4- (3-methoxyphenyl) -6-methylisoquinolin-1 -amine (17b);
3- (2,6-dimethylphenyl) -4- (3-methoxyphenyl) -6-methylisoquinolin-1 -amine (17c);
3- (2-methoxyphenyl) -4- (3-methoxyphenyl) isoquinolin-1 -amine (17d); or
4- (3-Methoxyphenyl) -3- (4-methoxyphenyl) isoquinolin-1 -amine (17e).
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| WO2011140228A1 (en) | 2010-05-04 | 2011-11-10 | Gtx, Inc. | Nuclear receptor binding agents |
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| WO2011140228A1 (en) | 2010-05-04 | 2011-11-10 | Gtx, Inc. | Nuclear receptor binding agents |
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| Title |
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| Martine Croisy-Delcey 외 8명. Diphenyl quinolines and isoquinolines: synthesis and primary biological evaluation. Bioorganic & Medicinal Chemistry. Vol. 8, No. 11, 2000, pp. 2629-2641* |
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