CN106588920B - 1,3- diazacyclos simultaneously [1,2-a] quinolines and preparation method thereof and antitumor application thereof - Google Patents
1,3- diazacyclos simultaneously [1,2-a] quinolines and preparation method thereof and antitumor application thereof Download PDFInfo
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Abstract
The present invention relates to 1,3- diazacyclos simultaneously [1,2-a] quinolines and preparation method thereof and antitumor application thereof, belong to field of pharmaceutical chemistry technology.The compound structure such as formula（Ⅰ）It is shown：Formula（Ⅰ）In, Ar refers to phenyl, halogenophenyl, alkyl-substituted phenyl, alkoxy substituted phenyl, trifluoromethyl substituted-phenyl, nitro substituted-phenyl, cyano substituted-phenyl or thienyl；R1~R4For halogen atom, hydrogen atom, alkyl, trifluoromethyl, nitro or piperidyl；N is 1 or 2 or 3.The present invention is by external people source tumor cell line screening active ingredients studies have shown that five kinds of common tumor cell lines of the compound of the present invention pair：HCT116, A549, HT29, SGC7901 and HepG2, all have very strong antitumor activity, and the antitumor activity of most compounds of the invention is better than positive control medicine cis-platinum.The present invention has wide utilization foreground in terms of preparing antitumor drug.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to one kind 1,3- diazacyclos with anti-tumor activity are simultaneously
[1,2-a] quinolines and preparation method thereof, and as the purposes of antitumor drug.
Background technology
With the development of society, environmental pollution and food problems getting worse, cancer, which has become, endangers human health
Primary disease.Seek a kind of effective, low toxicity and the easy anticancer drug prepared has become the emphasis of various countries' medicament research and development.Wherein
The cell toxicant kind anti-cancer drugs of extensive utilization mainly have metal platinum class complex compound, alkylating agents, antibiotics and adjust immune function
Class etc..
Colon-rectum is one of most common malignant tumour in China, occupies Cancer Mortality the 4th at present.In recent years
Come, the incidence of colorectal cancer is in apparent ascendant trend, this trend is more apparent in big and medium-sized cities.Equally it is most in western countries
One of common tumour.
And colon-rectum is usually less sensitive to current adoptable chemotherapy or is difficult to treat, for such cancer
The only effective reagent of disease is 5 FU 5 fluorouracil.When invalid to the polychemotherapy based on 5 FU 5 fluorouracil, currently without it
Its replacement treatment means.Therefore, to novel drugs of such cancer with good therapeutic effect for mitigating the slight illness of patient with weight
The realistic meaning wanted.
Quinoline is parent nucleus of many natural products and biologically active drug structure, such as quinine, chloroquine, camptothecine etc..With
The development of synthesis chemistry, substantial quinoline analog derivative is synthesized, and they have extensive bioactivity, such as：
Anti-malarial, antibacterial, anti-inflammatory, antitumor, anti-diabetic, anti-hypertension, AntiHIV1 RT activity etc..There are many quinolines chemical combination both at home and abroad
The patent report of object.
It is active with anti-lung cancer, inhibitor against colon carcinoma cells that WO2013000269 (Zhou Wenqiang) discloses a kind of camptothecin derivative.
CN201610480497.0 (Huang Shiliang) discloses a kind of 2- substitution aromatic ethylene base-N- quinolines that methylate and exists
Prepare the application in antitumor drug.
CN201610399172.X (Tang Dongfeng) disclose a kind of quinoline, quinazoline compounds and its pharmaceutical composition and
Using.
CN201610077368.7 (Zhou Youjun) discloses a kind of quinolines multiple target point kinases suppression with anti-tumor activity
Preparation and preparation method thereof.
US9493419 (Johnny Cheuk-on Tang) discloses a kind of quinolines chemical combination with anti-tumor activity
Object.
US4826850 (Masatoshi Yamato) discloses a kind of quinoline series antineoplastic medicament.
US5112817 (Nobuyuki Fukazawa) discloses a kind of quinolines with anti-tumor activity.
Invention content
The object of the present invention is to provide a kind of 1,3- diazacyclos with anti-tumor activity simultaneously [1,2-a] quinolines chemical combination
Object and preparation method thereof, and the purposes as antitumor drug.
To achieve the above object, the technical solution adopted by the present invention is as follows：
Simultaneously [1,2-a] quinolines, the structure such as formula (I) of the compound are shown for 1,3- diazacyclo：
Wherein, in formula (I), Ar refers to phenyl, halogenophenyl, alkyl-substituted phenyl, alkoxy substituted phenyl, trifluoromethyl and takes
For phenyl, nitro substituted-phenyl, cyano substituted-phenyl or thienyl；
R1~R4For halogen atom, hydrogen atom, alkyl, trifluoromethyl, nitro or piperidyl；
N is 1 or 2 or 3.
The present invention also provides the preparation method of above-mentioned 1,3- diazacyclos simultaneously [1,2-a] quinolines, including it is as follows
Step：
Existed with the 2- fluorobenzaldehyde class compounds of formula (II) structure and the heterocycle ketene peptide amine compound of formula (III) structure
It in solvent, is heated under alkaline condition or inorganic salts existence condition, carries out nucleophilic displacement of fluorine and condensation reaction to TLC detections and reacted
Quan Hou, purifying is to get to simultaneously [1, the 2-a] quinolines of 1,3- diazacyclos shown in formula (I)；
In formula (II), R1~R4For halogen atom, hydrogen atom, alkyl, trifluoromethyl, nitro or piperidyl；
In formula (III), Ar refers to phenyl, halogenophenyl, alkyl-substituted phenyl, alkoxy substituted phenyl, trifluoromethyl substitution
Phenyl, nitro substituted-phenyl, cyano substituted-phenyl or thienyl；N is 1 or 2 or 3.
It is further preferred that the solvent be methanol, ethyl alcohol, water, acetone, dichloromethane, chloroform, ethyl acetate,
The mixing of one or more of N,N-dimethylformamide, tetrahydrofuran, toluene, 1,4- dioxane and acetonitrile solvent is molten
Agent.
It is further preferred that the alkali is the mixture of one or more of piperidines, triethylamine and calcium oxide,
The molar ratio of alkali and the heterocycle ketene peptide amine compound of formula (III) structure is 1：0.5~2；The inorganic salts are calcium chloride,
The molar ratio of inorganic salts and the heterocycle ketene peptide amine compound of formula (III) structure is 1：0.5~2.
It is further preferred that heating temperature is 40~110 DEG C.
It is further preferred that the reaction time is 0.5~24 hour.
It is further preferred that the heterocyclic-ketene-aminal of the 2- fluorobenzaldehyde class compounds of formula (II) structure and formula (III) structure
The molar ratio of contracting aminated compounds is 1：1-3.
The present invention also provides above-mentioned 1,3- diazacyclos simultaneously [1,2-a] quinolines as preparing antitumor drug
Using.
Compared with prior art, the present invention advantage is：
The present invention is set out using the raw material simple and easy to get structure as shown in formula (II) with the structure as shown in formula (III), passes through one
Target compound with anti-tumor activity (I) is obtained by the reaction in step.The synthesis technology of the invention is simple, and yield is high, and product is stablized.
The invention realizes 1,3- of succinct, efficient parallel synthesis diazacyclos simultaneously [1,2-a] quinolines library, and really realizes
Molecular diversity.
Institute's invention compound has to people's knot-carcinoma of the rectum (HCT116), human lung cancer (A549), human colon carcinoma (HT29), people
Gastric cancer (SGC7901), human liver cancer (HepG2) preferable antitumor activity.Experimental study shows 2,17~28 pairs of compound
The IC of HCT116 cell strains50(μ g/mL) is respectively 4.75,4.06,6.35,5.00,4.48,5.06,5.32,6.38,7.70,
8.44,5.65,8.53,8.72, the respectively less than IC of cis-platinum50(μ g/mL)=8.74, and both less than 10 μ g/mL, it is aobvious relative to cis-platinum
Superior active anticancer is shown.Compound 17 and compound 21 are to HCT116 (the people's knot-carcinoma of the rectum), A549 (lung cancer), HT29 (knot
Intestinal cancer), SGC7901 (gastric cancer), HepG2 (liver cancer) cell strain all shows superior active anticancer, IC50Value is right much smaller than positive
According to the IC of drugs Cisplatin50Value, and both less than 10 μ g/mL.
Description of the drawings
Fig. 1 is the mono-crystalline structures figure of compound 49.
Specific implementation mode
With reference to embodiment, the present invention is described in further detail.
It will be understood to those of skill in the art that the following example is merely to illustrate the present invention, and it should not be regarded as limiting this hair
Bright range.In the examples where no specific technique or condition is specified, according to technology or condition described in document in the art
Or it is carried out according to product description.Production firm person is not specified in agents useful for same, instrument etc., is that can be obtained by buying
Conventional products.
Raw material of the present invention can be prepared by the well known method of this field or be obtained by commercial product.
The 1,3- diazacyclos of the present invention explained further below general side that simultaneously [1,2-a] quinolines synthesize
Method, but the preparation method of 1,3- of present invention diazacyclos simultaneously [1,2-a] quinolines is not limited to this.
Synthesizing 1,3- diazacyclos of the invention, simultaneously [1,2-a] quinolines method is as follows：
Existed with the 2- fluorobenzaldehyde class compounds of formula (II) structure and the heterocycle ketene peptide amine compound of formula (III) structure
In solvent, heated under alkaline condition or inorganic salts existence condition.TLC detections after purification, obtain pure formula (I) after the reaction was complete
Target product, specific reaction equation are as follows：
In formula (II), R1~R4 is halogen atom, hydrogen atom, alkyl, trifluoromethyl, nitro or piperidyl.
In formula (III), Ar refers to phenyl, halogenophenyl, alkyl-substituted phenyl, alkoxy substituted phenyl, trifluoromethyl substitution
Phenyl, nitro substituted-phenyl, cyano substituted-phenyl or thienyl；N is 1 or 2 or 3.
Way of purification is usually to filter after reaction, is washed with a small amount of solvent, takes solid to be extracted added with solvent and buck, so
After take organic phase to concentrate after be recrystallized to give product, but purification process of the present invention is without being limited thereto.
In reaction, solvent does not make concrete regulation, is often acetone, dichloromethane, chloroform, ethyl acetate, N, N- dimethyl methyls
The mixed solvent of one or more of amide, tetrahydrofuran, toluene, 1,4- dioxane and acetonitrile solvent；Alkali is not made specifically
Regulation is often piperidines, one or more of triethylamine and calcium oxide；Inorganic salts are calcium chloride；Reaction temperature is not advised specifically
It is fixed, often it is 40~110 DEG C；Reaction time does not make concrete regulation, is often 0.5~24 hour.Reaction process using TLC detect with
Track stops heating after the reaction was complete, product recrystallization or washing or extraction solvent do not make concrete regulation, and extractant is often chlorine
One kind in imitative, ethyl acetate and dichloromethane and sodium bicarbonate or aqueous sodium carbonate, recrystallization or cleaning solvent Chang Weiyi
The mixed solvent of the mixed solvent of acetoacetic ester and petroleum ether, chloroform and petroleum ether.
In reaction, for 1 mM of formula (III) compound, formula (II) compound amount is 1~3 mM.Reaction
Yield is generally 90~98%.
The compound of formula (II) is well known, or can be prepared according to known methods, and most of is commercially available.
The compound of formula (III) is well known, or can be prepared according to known methods.
The present invention is from heterocyclic ketene semiamine shown in 2- fluorobenzaldehyde class compounds and formula (III) shown in the starting materials of formulae that is easy to get (II)
Class compound is set out, and a series of new 1,3- diazacyclos of one pot process simultaneously [1,2-a] quinolines (I) are passed through.
Human tumor cell line experiment is carried out to the compound of the present invention：HCT116 (Human colorectal carcinoma), A549 (lung cancer),
HT29 (colon cancer), SGC7901 (gastric cancer), HepG2 (liver cancer).By cell tests compound incubation 144 hours, then use
MTT measuring methods measure cytotoxicity (" the fast speed ratio of cell viability of Mossman, T.J.Immunol.Methods 1983,65,55
Color method of testing；Cytotoxicity and the quantitative application of growth inhibition lymphokine ".Green, L.M.J.Immunol.Methods
1984,70,257 " the quick colorimetric tests of cell viability；Cytotoxicity and the quantitative application of growth inhibition lymphokine ").
The data obtained confirms that the compound of the present invention has apparent work to entity tumor, particularly lung cancer and colorectal cancer
Property.
The day dosage of the compounds of this invention is 0.01mg-10mg/kg.Preferred day dosage be about 0.2mg extremely
2mg/kg weight, for the patient of weight about 70kg, using the single dose administration about 14mg to about 140mg in 24 hours
Active material.The dosage range can be adjusted to obtain better therapeutic effect.The reactive compound of the present invention can pass through
The modes such as oral, intravenous administration, intramuscular administration, subcutaneous administration are administered.
The compound of the present invention can increase describedization with other reagent combination medicine-feedings for leading to tumour regression with collaboration
Close the antitumous effect of object.The compound of the present invention can respectively from different anticancer drugs, such as：Cis-platinum, husky sharp platinum, 5- fluorine urine are phonetic
Pyridine, adriamycin, gemcitabine, taxol, vincristine, hydroxycamptothecin, topotecan, irinotecan combination administration (combination
Administration ratio 1：10~10：1).
The pharmaceutical composition of the present invention includes that the compound of at least one invention of therapeutically effective amount is mixed with pharmaceutical
Object.
Orally administered composition includes capsule, tablet, pill, suspension or the syrup suitable for oral medication.
For the pharmaceutical composition for preparing for parenteral administration, active constituent can be mixed in solution or suspension.
The present invention is described in detail with reference to part specific embodiment.These embodiments are merely to illustrate the present invention,
Rather than it limits the scope of the invention.Preparation method in embodiment is only preferred embodiment, but the invention is not limited in excellent
Select preparation method.
First part's synthetic example
Embodiment 1：Synthesize 4- (4- fluoro benzoyls) -7- nitro -1,2- glyoxalidine simultaneously [1,2-a] quinoline (compound
1)
1- (4- fluorophenyls) -2- (imidazolidine -2- subunits) second -1- ketone (1 mM) is added in 25 milliliters of round-bottomed flasks
After the fluoro- 5- nitrobenzaldehydes of 2- (3 mMs), Isosorbide-5-Nitrae-dioxane (15 milliliters) and piperidines (1 mM) magnetic force is added and stirs
It mixes down and is heated at 65 DEG C, react 2 hours.Petroleum ether/dichloromethane=10 are used after filtering:1 mixed solvent washing precipitation, obtains
Yellow fluffy solid.Extracting yellow solid is added chloroform and saturated sodium bicarbonate aqueous solution, takes organic phase to be saturated after extraction
Sodium-chloride water solution washs, and collects chloroform and is dried with anhydrous sodium sulfate, and petroleum ether recrystallization is added after partial solvent is evaporated off,
Dry yellow solid product 4- (4- fluoro benzoyls) -7- nitro -1,2- glyoxalidine simultaneously (change by [1,2-a] quinoline after filtering
Close object 1), yield 94%.Fusing point：229~230 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated dimethyl sulfoxide, 300 instrument of Bruker AM):δ=3.88-3.95 (m, 2H, CH2N),
4.01-4.08 (m, 2H, NCH2), 6.98 (d, J=9.3Hz, 1H, ArH), 7.35 (t, J=8.9Hz, 2H, ArH), 7.80 (s,
1H, CH), 7.97-8.02 (m, 2H, ArH), 8.24-8.28 (m, 1H, ArH), 8.45 (d, J=2.4Hz, 1H, ArH).
Carbon-13 nmr spectra (deuterated dimethyl sulfoxide, 300 instrument of Bruker AM):δ=45.5,53.5,112.4,115.8
(d, J=21.8Hz), 119.1,124.9,127.2 129.4,132.4,132.6 (d, J=9.8Hz), 136.2,139.5,
143.9,152.8,165.4 (d, J=251.3Hz), 190.9.
High resolution mass spectrum C18H13FN3O3[M+H]+, theoretical value 338.0935；Measured value, 338.0935.
Embodiment 2：Synthesize three fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinolines of 5- (4- chlorobenzene formacyls) -7,8,10-
Quinoline (compound 2)
1- (4- chlorphenyls) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone (1 milli is added in 25 milliliters of round-bottomed flasks
Mole, 0.44 gram) and 2, after 3,5,6- tetrafluorobenzene carbaldehydes (3 mMs, 0.44 gram), (15 milliliters) works of Isosorbide-5-Nitrae-dioxane are added
For solvent, catalyst piperidines (0.5 mM) is added and anhydrous calcium chloride (0.5 mM) is heated to 110 under magnetic stirring
DEG C, it reacts 12 hours.Petrol ether/ethyl acetate=10 are used after filtering:1 mixed solvent washing precipitation, takes precipitation, is added later
It is washed with saturated sodium bicarbonate aqueous solution after ethyl acetate dissolving, organic phase is taken to be washed with saturated sodium-chloride water solution.Collect second
It is dried with anhydrous sodium sulfate after acetoacetic ester, appropriate petroleum ether is added after partial solvent is evaporated off to there is precipitation to generate, filters to take solid
Three fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinoline of yellow product 5- (4- chlorobenzene formacyls) -7,8,10- is obtained after soma is dry
(compound 2), yield 95%.Fusing point：199~199.5 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated dimethyl sulfoxide+perchloric acid, 600 instrument of Bruker AM):δ=2.16 (m, 2H, CH2),
3.54 (m, 2H, CH2N), 4.67 (m, 2H, NCH2), 7.71 (d, J=8.2Hz, 2H, ArH), 7.99 (d, J=8.3Hz, 2H,
ArH), 8.26-8.31 (m, 1H, A rH), 8.48 (s, 1H, CH).
Carbon-13 nmr spectra (deuterated dimethyl sulfoxide+perchloric acid, 600 instrument of Bruker AM):δ=18.3,39.1,50.8
(d, J=19.5Hz), 112.7 (m), 113.6 (d, J=16.5Hz), 124.8,125.1,129.6,132.7,134.9,
135.1,140.3,143.5 (d, J=6.3Hz), 145.6,146.8,150.7,190.9.
Enantiomeric excess (deuterated dimethyl sulfoxide+perchloric acid, 600 instrument of Bruker AM):δ=- 145.3 (m), -138.3
(m), -115.8.
High resolution mass spectrum C19H13ClF3N2O[M+H]+, theoretical value 377.0663；Measured value, 377.0665.
Embodiment 3：Synthesize 5- (4- chlorobenzene formacyls) -8- (trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline
Quinoline (compound 3)
1- (4- chlorphenyls) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone (1 milli is added in 25 milliliters of round-bottomed flasks
Mole) and 2- fluoro- 5- (trifluoromethyl) benzaldehyde (2 mMs) after, (15 milliliters) of Isosorbide-5-Nitrae-dioxane is added and is used as solvent, adds
Enter catalyst piperidines (0.5 mM) and anhydrous calcium chloride (0.5 mM) is heated to 75 DEG C under magnetic stirring, reaction 6 is small
When.With a small amount of petroleum ether/chloroform=10 after filtering:2 mixed solvent washing precipitation, takes precipitation to be dissolved with dichloromethane later,
Organic layer is washed successively with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution.Chloroform is collected later with anhydrous sulphur
Sour sodium drying is added appropriate hexamethylene to there is precipitation to generate, yellow production is obtained after filtering to take solid drying after partial solvent is evaporated off
Product 5- (4- chlorobenzene formacyls) -8- (trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (compound 3), yield
96%.Fusing point：181~182 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated dimethyl sulfoxide, 300 instrument of Bruker AM):δ=1.85-1.88 (m, 2H, CH2),
3.22-3.26 (m, 2H, CH2N), 3.89-3.92 (m, 2H, NCH2), 7.37 (d, J=8.7Hz, 1H, ArH), 7.51 (s, 1H,
CH), 7.55 (d, J=8.4Hz, 2H, ArH), 7.75 (d, J=9.0Hz, 1H, ArH), 7.87-7.90 (m, 3H, ArH).
Carbon-13 nmr spectra (deuterated dimethyl sulfoxide, 300 instrument of Bruker AM):δ=19.5,43.0,43.9,112.1,
119.5,121.0 (d, J=33.0Hz), 124.3 (d, J=270.0Hz), 125.8,127.0,128.8,130.4,130.8,
134.9,136.2,138.2,143.4,146.8,193.2.
High resolution mass spectrum C20H15ClF3N2O[M+H]+, theoretical value 391.0820；Measured value, 391.0816.
Embodiment 4：Synthesize 4- (4- chlorobenzene formacyls) 7- nitro -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound
4)
1- (4- fluorophenyls) -2- in embodiment 1 is replaced with 1- (4- chlorphenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(imidazolidine -2- subunits) second -1- ketone, uses Isosorbide-5-Nitrae-dioxane in ethyl alcohol alternate embodiment 1 as reaction dissolvent, at 40 DEG C
Reaction 12 hours, yellow solid 4- (4- chlorobenzene formacyls) 7- nitros -1,2- dihydro-imidazol can be obtained, and simultaneously [1,2-a] quinoline (is changed
Close object 4), yield 98%.Fusing point：273~278 DEG C.
High resolution mass spectrum C18H13ClN3O3[M+H]+, theoretical value 354.0640；Measured value, 354.0638.
Embodiment 5：Synthesize 4- (4- benzoyl bromides) (7- nitro -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compounds
5)
1- (4- fluorophenyls) -2- in embodiment 1 is replaced with 1- (4- bromophenyls) -2- (imidazolidine -2- subunits) second -1- ketone
It is available to carry out reaction with the piperidines in triethylamine (0.75 mM) alternate embodiment 1 for (imidazolidine -2- subunits) second -1- ketone
Yellow solid 4- (4- benzoyl bromides) (7- nitros -1,2- dihydro-imidazol simultaneously [1,2-a] quinoline (compound 5), yield 97%.
Fusing point：282~283 DEG C.
High resolution mass spectrum C18H13BrN3O3[M+H]+, theoretical value 398.0135；Measured value, 398.0137.
Embodiment 6：Synthesize 4- benzoyl -7- nitro -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 6)
1- (4- fluorophenyls) -2- (miaows in embodiment 1 are replaced with 2- (imidazolidine -2- subunits) -1- diphenylphosphino ethane -1- ketone
Oxazolidine -2- subunits) second -1- ketone, and anhydrous calcium chloride (0.5 mM) is added, it reacts 30 minutes, yellow solid 4- benzene can be obtained
Formoxyl -7- nitros -1,2- dihydro-imidazol simultaneously [1,2-a] quinoline (compound 6), yield 97%.Fusing point：285~286 DEG C.
High resolution mass spectrum C18H14N3O3[M+H]+, theoretical value 320.1030；Measured value, 320.1029.
Embodiment 7：4- is synthesized to toluyl groups -7- nitro -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 7)
1- (4- fluorophenyls) -2- in embodiment 1 is replaced with 2- (imidazolidine -2- subunits) -1- (p-methylphenyl) second -1- ketone
(imidazolidine -2- subunits) second -1- ketone, and calcium oxide (0.5 mM) is added, it carries out reaction and yellow solid 4- can be obtained to toluene
Formoxyl -7- nitros -1,2- dihydro-imidazol simultaneously [1,2-a] quinoline (compound 7), yield 95%.Fusing point：283~284 DEG C.
High resolution mass spectrum C19H16N3O3[M+H]+, theoretical value 334.1186；Measured value, 334.1186.
Embodiment 8：Synthesizing 4- (4- methoxybenzoyls base) -7- nitro -1,2- dihydro-imidazols, simultaneously [1,2-a] quinoline (is changed
Close object 8)
1- (the 4- fluorobenzene in embodiment 1 is replaced with 2- (imidazolidine -2- subunits) -1- (4- methoxyphenyls) second -1- ketone
Base) -2- (imidazolidine -2- subunits) second -1- ketone, Isosorbide-5-Nitrae-dioxy six in the mixed solvent alternate embodiment 1 of second alcohol and water is used in combination
Ring reacts 24 hours as solvent, yellow solid 4- (4- methoxybenzoyls base) -7- nitro -1,2- dihydro-imidazols can be obtained
And [1,2-a] quinoline (compound 8), yield 93%.Fusing point：260~261 DEG C.
High resolution mass spectrum C19H16N3O4[M+H]+, theoretical value 350.1135；Measured value, 350.1132.
Embodiment 9：Synthesize 4- (2- Thenoyls) -7- nitro -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound
9)
The 1- (4- fluorophenyls)-in embodiment 1 is replaced with 2- (imidazolidine -2- subunits) -1- (thiophene -2- bases) second -1- ketone
2- (imidazolidine -2- subunits) second -1- ketone, and Isosorbide-5-Nitrae-dioxane in water consumption substitution embodiment 1, as solvent, reaction 24 is small
When, orange solids 4- (2- Thenoyls) -7- nitros -1,2- dihydro-imidazol simultaneously [1,2-a] quinoline (compound 9) can be obtained,
Yield 90%.Fusing point：274~275 DEG C.
High resolution mass spectrum C16H12N3O3S[M+H]+, theoretical value 326.0594；Measured value, 326.0595.
Embodiment 10：5- (4- fluoro benzoyls) -8- nitro -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline is synthesized (to change
Close object 10)
1- (the 4- fluorobenzene in embodiment 1 is replaced with 1- (4- fluorophenyls) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone
Base) -2- (imidazolidine -2- subunits) second -1- ketone, in the mixed solvent alternate embodiment 1 of ethyl alcohol, Isosorbide-5-Nitrae-dioxane and toluene
Isosorbide-5-Nitrae-dioxane as solvent, carry out reaction and yellow solid 5- (4- fluoro benzoyls) -8- nitros -2,3- bis- can be obtained
Hydrogen -1H- pyrimidos [1,2-a] quinoline (compound 10), yield 94%.Fusing point：225–226℃.
High resolution mass spectrum C19H15FN3O3[M+H]+, theoretical value 352.1092；Measured value, 352.1088.
Embodiment 11：5- (4- chlorobenzene formacyls) -8- nitro -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline is synthesized (to change
Close object 11)
1- (the 4- fluorobenzene in embodiment 1 is replaced with 1- (4- chlorphenyls) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone
Base)-2- (imidazolidine-2- subunits) second-1- ketone carry out reaction yellow solid 5- (4- chlorobenzene formacyls) nitro-2-8- can be obtained,
3- dihydro -1H- pyrimidos [1,2-a] quinoline (compound 11), yield 96%.Fusing point：272~273 DEG C.
High resolution mass spectrum C19H15ClN3O3[M+H]+, theoretical value 368.0796；Measured value 368.0795.
Embodiment 12：5- (4- benzoyl bromides) -8- nitro -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline is synthesized (to change
Close object 12)
1- (the 4- fluorobenzene in embodiment 1 is replaced with 1- (4- bromophenyls) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone
Base)-2- (imidazolidine-2- subunits) second-1- ketone carry out reaction yellow solid 5- (4- benzoyl bromides) nitro-2-8- can be obtained,
3- dihydro -1H- pyrimidos [1,2-a] quinoline (compound 12), yield 95%.Fusing point：264~265 DEG C.
High resolution mass spectrum C19H15BrN3O3[M+H]+, theoretical value 412.0291；Measured value, 412.0291.
Embodiment 13：Synthesize 5- benzoyls -8- nitros -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (compound
13)
1- (4- fluorophenyls) -2- in embodiment 1 is replaced with 1- phenyl -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone
(imidazolidine -2- subunits) second -1- ketone carries out reaction, and that yellow solid 5- benzoyl -8- nitro -2,3- dihydros -1H- can be obtained is phonetic
Pyridine simultaneously [1,2-a] quinoline (compound 13), yield 96%.Fusing point：285~286 DEG C.
High resolution mass spectrum C19H16N3O3[M+H]+, theoretical value 334.1186；Measured value, 334.1186.
Embodiment 14：5- is synthesized to toluyl groups -8- nitros -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (chemical combination
Object 14)
1- (the 4- fluorobenzene in embodiment 1 is replaced with 2- (tetrahydropyrimidine -2 (1H)-subunit) -1- (p-methylphenyl) second -1- ketone
Base) -2- (imidazolidine -2- subunits) second -1- ketone carry out reaction yellow solid 5- can be obtained to toluyl groups -8- nitros -2,3-
Dihydro -1H- pyrimidos [1,2-a] quinoline (compound 14), yield 92%.Fusing point：281~282 DEG C.
High resolution mass spectrum C20H18N3O3[M+H]+, theoretical value 348.1343；Measured value, 348.1341.
Embodiment 15：Synthesize 5- (4- methoxybenzoyls base) -8- nitros -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline
Quinoline (compound 15)
1- (the 4- in embodiment 1 are replaced with 1- (4- methoxyphenyls) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone
Fluorophenyl) -2- (imidazolidine -2- subunits) second -1- ketone carry out reaction yellow solid 5- (4- methoxybenzoyls base) -8- can be obtained
Nitro -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (compound 15), yield 91%.Fusing point：221~222 DEG C.
High resolution mass spectrum C20H18N3O4[M+H]+, theoretical value 364.1292；Measured value, 364.1293.
Embodiment 16：5- (2- Thenoyls) -8- nitro -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline is synthesized (to change
Close object 16)
1- (the 4- fluorine in embodiment 1 is replaced with 2- (tetrahydropyrimidine -2 (1H)-subunit) -1- (thiophene -2- bases) second -1- ketone
Phenyl) -2- (imidazolidine -2- subunits) second -1- ketone carry out reaction orange/yellow solid 5- (2- Thenoyls) -8- nitre can be obtained
Base -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (compound 16), yield 91%.Fusing point：274~275 DEG C.
High resolution mass spectrum C17H14N3O3S[M+H]+, theoretical value 340.0750；Measured value, 340.0752.
Embodiment 17：Synthesize 6- (4- chlorobenzene formacyls) -9- nitro -1,2,3,4- tetrahydrochysenes-[1,3] diazepine simultaneously [1,
2-a] quinoline (compound 17)
1- (the 4- in embodiment 1 are replaced with 1- (4- chlorphenyls) -2- (1,3- Diazesuberane -2- subunits) second -1- ketone
Fluorophenyl) -2- (imidazolidine -2- subunits) second -1- ketone carry out reaction yellow solid 6- (4- chlorobenzene formacyls) -9- nitre can be obtained
Base -1,2,3,4- tetrahydrochysenes-[1,3] diazepine simultaneously [1,2-a] quinoline (compound 17), yield 93%.Fusing point：232~233
℃。
High resolution mass spectrum C20H17ClN3O3[M+H]+, theoretical value 382.0953；Measured value, 382.0952.
Embodiment 18：6- is synthesized to toluyl groups -9- nitro -1,2,3,4- tetrahydrochysenes-[1,3] diazepine simultaneously [1,2-
A] quinoline (compound 18)
1- (the 4- in embodiment 1 are replaced with 2- (1,3- Diazesuberane -2- subunits) -1- (p-methylphenyl) second -1- ketone
Fluorophenyl) -2- (imidazolidine -2- subunits) second -1- ketone carry out reaction yellow solid 6- can be obtained to toluyl groups -9- nitros -
1,2,3,4- tetrahydrochysene-[1,3] diazepine simultaneously [1,2-a] quinoline (compound 18), yield 92%.Fusing point：238~239 DEG C.
High resolution mass spectrum C21H20N3O3[M+H]+, theoretical value 362.1499；Measured value, 362.1500.
Embodiment 19：Synthesize three fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols of 4- (4- fluoro benzoyls) -6,7,9-
And [1,2-a] quinoline (compound 19)
1- (4- fluorophenyls) -2- (imidazolidine -2- subunits) second -1- ketone (1 mM) is added in 25 milliliters of round-bottomed flasks
With 2, after 3,4,5,6- pentafluorobenzaldehydes (2 mMs), Isosorbide-5-Nitrae-dioxane (15 milliliters) and piperidines (1.5 mMs) is added,
And anhydrous CaCl2(1.2 mMs) are heated to 101 DEG C of reflux under magnetic agitation, react 8 hours.It is dark red to negate lower layer after answering
Color grease is added chloroform and saturated aqueous sodium carbonate, takes organic phase to be washed with saturated sodium-chloride water solution after extraction,
It collects chloroform to dry with anhydrous sodium sulfate, petroleum ether recrystallization is added after partial solvent is evaporated off, it is redly dry after filtering
Three fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols of solid product 4- (4- fluoro benzoyls) -6,7,9- simultaneously [1,2-a] quinoline
(compound 19), yield 92%.Fusing point：170~171 DEG C.
High resolution mass spectrum C23H20F4N3O[M+H]+, theoretical value 430.1537；Measured value, 430.1533.
Embodiment 20：Synthesize three fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols of 4- (4- chlorobenzene formacyls) -6,7,9-
And [1,2-a] quinoline (compound 20)
The 1- (4- fluorophenyls)-in embodiment 19 is replaced with 1- (4- chlorphenyls) -2- (imidazolidine -2- subunits) second -1- ketone
2- (imidazolidine -2- subunits) second -1- ketone uses Isosorbide-5-Nitrae-dioxane in toluene alternate embodiment 19 as solvent, anti-at 110 DEG C
It answers 6 hours, red solid 4- (4- chlorobenzene formacyls) -6,7,9- tri- fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols can be obtained
And [1,2-a] quinoline (compound 20), yield 93%.Fusing point：160~161 DEG C.
High resolution mass spectrum C23H20ClF3N3O[M+H]+, theoretical value 446.1242；Measured value, 446.1239.
Embodiment 21：Synthesize three fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols of 4- (4- benzoyl bromides) -6,7,9-
And [1,2-a] quinoline (compound 21)
The 1- (4- fluorophenyls)-in embodiment 19 is replaced with 1- (4- bromophenyls) -2- (imidazolidine -2- subunits) second -1- ketone
2- (imidazolidine -2- subunits) second -1- ketone, with the CaCl in CaO alternate embodiments 192, carry out reaction and orange solids 4- can be obtained
(4- benzoyl bromides) -6,7,9- tri- fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 21),
Yield 92%.Fusing point：181~182 DEG C.
High resolution mass spectrum C23H20BrF3N3O[M+H]+, theoretical value 490.0735；Measured value, 490.0737.
Embodiment 22：Synthesize three fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols of 4- benzoyls -6,7,9- simultaneously [1,2-
A] quinoline (compound 22)
1- (4- fluorophenyls) -2- (miaows in embodiment 19 are replaced with 2- (imidazolidine -2- subunits) -1- diphenylphosphino ethane -1- ketone
Oxazolidine -2- subunits) second -1- ketone carry out reaction three fluoro- 8- (piperidines -1- of Orange red solid 4- benzoyls -6,7,9- can be obtained
Base) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 22), yield 93%.Fusing point：186~187 DEG C.
High resolution mass spectrum C23H21F3N3O[M+H]+, 412.1631 measured value of theoretical value, 412.1633.
Embodiment 23：Synthesize 4- to three fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols of toluyl groups -6,7,9- simultaneously
[1,2-a] quinoline (compound 23)
The 1- (4- fluorophenyls)-in embodiment 19 is replaced with 2- (imidazolidine -2- subunits) -1- (p-methylphenyl) second -1- ketone
2- (imidazolidine -2- subunits) second -1- ketone carries out reaction and yellow solid 4- can be obtained to three fluoro- 8- (piperazines of toluyl groups -6,7,9-
Pyridine -1- bases) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 23), yield 92%.Fusing point：136~137 DEG C.
High resolution mass spectrum C24H23F3N3O[M+H]+, theoretical value 426.1788；Measured value, 326.1789.
Embodiment 24：Synthesize three fluoro- 8- (piperidin-1-yl) -1,2- dihydros of 4- (4- methoxybenzoyls base) -6,7,9- -
Imidazo [1,2-a] quinoline (compound 24)
1- (the 4- fluorobenzene in embodiment 19 is replaced with 2- (imidazolidine -2- subunits) -1- (4- methoxyphenyls) second -1- ketone
Base) -2- (imidazolidine -2- subunits) second -1- ketone carry out reaction Orange red solid 4- (4- methoxybenzoyls base) -6,7 can be obtained,
Tri- fluoro- 8- (piperidin-1-yl) of 9- -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 24), yield 91%.Fusing point：167~
168℃。
High resolution mass spectrum C24H23F3N3O2[M+H]+, theoretical value 442.1737；Measured value, 442.1737.
Embodiment 25：Synthesize three fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinolines of 5- (4- fluoro benzoyls) -7,8,10-
Quinoline (compound 25)
1- (the 4- chlorobenzenes in embodiment 2 are replaced with 1- (4- fluorophenyls) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone
Base) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone, it is used in combination Isosorbide-5-Nitrae-dioxane in methanol alternate embodiment 2 as molten
Agent is reacted 8 hours at 50 DEG C, and yellow solid 5- (4- fluoro benzoyls) -7,8,10- tri- fluoro- 2,3- dihydros -1H- can be obtained
Pyrimido [1,2-a] quinoline (compound 25), yield 92%.Fusing point：179℃.
High resolution mass spectrum C19H13F4N2O[M+H]+, theoretical value 361.0959；Measured value, 361.0959.
Embodiment 26：Synthesize three fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinolines of 5- (4- benzoyl bromides) -7,8,10-
Quinoline (compound 26)
1- (the 4- chlorobenzenes in embodiment 2 are replaced with 1- (4- bromophenyls) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone
Base) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone, it is used in combination Isosorbide-5-Nitrae-dioxane in acetone alternate embodiment 2 as molten
Agent is reacted 24 hours at 40 DEG C, and -7,8,10- tri- fluoro- 2,3- bis- of yellow solid 5- (4- benzoyl bromides) can be obtained in reaction
Hydrogen -1H- pyrimidos [1,2-a] quinoline (compound 26), yield 95%.Fusing point：193~194 DEG C.
High resolution mass spectrum C19H13BrF3N2O[M+H]+, theoretical value 421.0158；Measured value, 421.1059.
Embodiment 27：Three fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinoline of 5- benzoyls -7,8,10- is synthesized (to change
Close object 27)
1- (4- chlorphenyls) -2- in embodiment 2 is replaced with 1- phenyl -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone
(tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone, is used in combination Isosorbide-5-Nitrae-dioxane in acetone alternate embodiment 2 as solvent, 40
It is reacted 24 hours at DEG C, carries out reaction and yellow solid 5- benzoyls -7,8, tri- fluoro- 2,3- dihydros -1H- pyrimidines of 10- can be obtained
And [1,2-a] quinoline (compound 27), yield 94%.Fusing point：191~192 DEG C.
High resolution mass spectrum C19H14F3N2O[M+H]+, theoretical value 343.1053；Measured value, 343.1054.
Embodiment 28：5- is synthesized to three fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinoline of toluyl groups -7,8,10-
(compound 28)
1- (the 4- chlorobenzenes in embodiment 2 are replaced with 2- (tetrahydropyrimidine -2 (1H)-subunit) -1- (p-methylphenyl) second -1- ketone
Base) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone, the Isosorbide-5-Nitrae-two in n,N-Dimethylformamide alternate embodiment 2 is used in combination
Six ring of oxygen carries out reaction and yellow solid 5- can be obtained to toluyl groups -7,8, tri- fluoro- 2,3- dihydros -1H- of 10- as solvent
Pyrimido [1,2-a] quinoline (compound 28), yield 92%.Fusing point：196~197 DEG C.
High resolution mass spectrum C20H16F3N2O[M+H]+, theoretical value 357.1209；Measured value, 357.1208.
Embodiment 29：Synthesize three fluoro- 2,3- dihydros -1H- pyrimidos [1,2- of 5- (4- methoxybenzoyls base) -7,8,10-
A] quinoline (compound 29)
1- (the 4- in embodiment 2 are replaced with 1- (4- methoxyphenyls) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone
Chlorphenyl) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carry out reaction yellow solid 5- (4- methoxybenzoyls can be obtained
Base) -7,8,10- tri- fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinoline (compound 29), yield 90%.Fusing point：174~
175℃。
High resolution mass spectrum C20H16F3N2O2[M+H]+, theoretical value 373.1158；Measured value, 373.1158.
Embodiment 30：Synthesize three fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinolines of 5- (2- Thenoyls) -7,8,10-
Quinoline (compound 30)
1- (the 4- chlorine in embodiment 2 is replaced with 2- (tetrahydropyrimidine -2 (1H)-subunit) -1- (thiophene -2- bases) second -1- ketone
Phenyl) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carry out reaction yellow solid 5- (2- Thenoyls) -7 can be obtained,
8,10- tri- fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinoline (compound 30), yield 91%.Fusing point：178~179 DEG C.
High resolution mass spectrum C17H12F3N2OS[M+H]+, theoretical value 349.0617；Measured value, 349.0618.
Embodiment 31：Synthesize three fluoro- 1,2- dihydro-imidazols of 4- (4- fluoro benzoyls) -6,7,9- simultaneously [1,2-a] quinoline
(compound 31)
1- (4- chlorphenyls) -2- in embodiment 2 is replaced with 1- (4- fluorophenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carries out reaction and red solid 4- (4- fluoro benzoyls) -6,7,9- three can be obtained
Fluoro- 1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 31), yield 93%.Fusing point：178~179 DEG C.
High resolution mass spectrum C18H11F4N2O[M+H]+, theoretical value 347.0802；Measured value, 347.0801.
Embodiment 32：Synthesize three fluoro- 1,2- dihydro-imidazols of 4- (4- chlorobenzene formacyls) -6,7,9- simultaneously [1,2-a] quinoline
(compound 32)
1- (4- chlorphenyls) -2- in embodiment 2 is replaced with 1- (4- chlorphenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carries out reaction and red solid 4- (4- chlorobenzene formacyls) -6,7,9- three can be obtained
Fluoro- 1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 32), yield 95%.Fusing point：176~177 DEG C.
High resolution mass spectrum C18H11ClF3N2O[M+H]+, theoretical value 363.0507；Measured value, 363.0503.
Embodiment 33：Synthesize three fluoro- 1,2- dihydro-imidazols of 4- (4- benzoyl bromides) -6,7,9- simultaneously [1,2-a] quinoline
(compound 33)
1- (4- chlorphenyls) -2- in embodiment 2 is replaced with 1- (4- bromophenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carries out reaction and orange solids 4- (4- benzoyl bromides) -6,7,9- three can be obtained
Fluoro- 1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 33), yield 94%.Fusing point：203~204 DEG C.
High resolution mass spectrum C18H12BrF3N2O[M+H]+, theoretical value 407.0001；Measured value, 407.0000.
Embodiment 34：Synthesize three fluoro- 1,2- dihydro-imidazols of 4- benzoyls -6,7,9- simultaneously [1,2-a] quinoline (compound
34)
1- (4- chlorphenyls) -2- (four in embodiment 2 is replaced with 2- (imidazolidine -2- subunits) -1- diphenylphosphino ethane -1- ketone
Hydrogen pyrimidine -2 (1H)-subunit) second -1- ketone carry out reaction three fluoro- 1,2- bis- of orange solids 4- benzoyls -6,7,9- can be obtained
Hydrogen-imidazo [1,2-a] quinoline (compound 34), yield 94%.Fusing point：195~196 DEG C.
High resolution mass spectrum C18H12F3N2O[M+H]+, theoretical value 329.0896；Measured value, 329.0894.
Embodiment 35：Synthesizing 4-, simultaneously [1,2-a] quinoline (is changed to three fluoro- 1,2- dihydro-imidazols of toluyl groups -6,7,9-
Close object 35)
1- (4- chlorphenyls) -2- in embodiment 2 is replaced with 2- (imidazolidine -2- subunits) -1- (p-methylphenyl) second -1- ketone
(tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carries out reaction and Orange red solid 4- can be obtained to toluyl groups -6,7,9- three
Fluoro- 1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 35), yield 92%.Fusing point：185~186 DEG C.
High resolution mass spectrum C19H14F3N2O[M+H]+, theoretical value 343.1053；Measured value, 343.1050.
Embodiment 36：Synthesize three fluoro- 1,2- dihydro-imidazols of 4- (4- methoxybenzoyls base) -6,7,9- simultaneously [1,2-a] quinoline
Quinoline (compound 36)
1- (the 4- chlorobenzenes in embodiment 2 are replaced with 2- (imidazolidine -2- subunits) -1- (4- methoxyphenyls) second -1- ketone
Base) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carry out reaction orange solids 4- (4- methoxybenzoyls base)-can be obtained
6,7,9- tri- fluoro- 1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 36), yield 93%.Fusing point：192~193 DEG C.
High resolution mass spectrum C19H14F3N2O2[M+H]+, theoretical value 359.1002；Measured value 359.0999.
Embodiment 37：Synthesize three fluoro- 1,2- dihydro-imidazols of 4- (2- Thenoyls) -6,7,9- simultaneously [1,2-a] quinoline
(compound 37)
The 1- (4- chlorphenyls)-in embodiment 2 is replaced with 2- (imidazolidine -2- subunits) -1- (thiophene -2- bases) second -1- ketone
2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carries out reaction and orange solids 4- (2- Thenoyls) -6,7,9- three can be obtained
Fluoro- 1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 37), yield 92%.Fusing point：170~171 DEG C.
High resolution mass spectrum C16H10F3N2OS[M+H]+, theoretical value 335.0460；Measured value 335.0464.
Embodiment 38：Synthesize 5- (4- fluoro benzoyls) -8- (trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,2-a]
Quinoline (compound 38)
1- (the 4- chlorobenzenes in embodiment 3 are replaced with 1- (4- fluorophenyls) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone
Base) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carry out reaction light yellow solid 5- (4- fluoro benzoyls) -8- can be obtained
(trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (compound 38), yield 94%.Fusing point：172~173 DEG C.
High resolution mass spectrum C20H15F4N2O[M+H]+, theoretical value 3375.1115；Measured value, 375.1113.
Embodiment 39：Synthesize 5- (4- benzoyl bromides) -8- (trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,2-a]
Quinoline (compound 39)
1- (the 4- chlorobenzenes in embodiment 3 are replaced with 1- (4- bromophenyls) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone
Base) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carry out reaction light yellow solid 5- (4- benzoyl bromides) -8- can be obtained
(trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (compound 39), yield 96%.Fusing point：195~196 DEG C.
High resolution mass spectrum C20H15BrF3N2O[M+H]+, theoretical value 435.0314；Measured value, 435.0317.
Embodiment 40：5- benzoyls -8- (trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline is synthesized (to change
Close object 40)
1- (4- chlorphenyls) -2- in embodiment 2 is replaced with 1- phenyl -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone
(tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carries out reaction and light yellow solid 5- benzoyls -8- (trifluoromethyl)-can be obtained
2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (compound 40), yield 95%.Fusing point：187~188 DEG C.
High resolution mass spectrum C20H16F3N2O[M+H]+, theoretical value 357.1209；Measured value, 357.1205.
Embodiment 41：5- is synthesized to toluyl groups -8- (trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline
Quinoline (compound 41)
1- (the 4- chlorobenzenes in embodiment 3 are replaced with 2- (tetrahydropyrimidine -2 (1H)-subunit) -1- (p-methylphenyl) second -1- ketone
Base) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carry out reaction light yellow solid 5- can be obtained to toluyl groups -8-
(trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (compound 41), yield 94%.Fusing point：226~227 DEG C.
High resolution mass spectrum C21H18F3N2O[M+H]+, theoretical value 371.1366；Measured value, 371.1363.
Embodiment 42：Synthesis 5- (4- methoxybenzoyls base) -8- (trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,
2-a] quinoline (compound 42)
1- (the 4- in embodiment 3 are replaced with 1- (4- methoxyphenyls) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone
Chlorphenyl) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carry out reaction white solid 5- (4- methoxybenzoyls can be obtained
Base) -8- (trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (compound 42), yield 93%.Fusing point：191~
192℃。
High resolution mass spectrum C21H18F3N2O2[M+H]+, theoretical value 387.1315；Measured value 387.1317.
Embodiment 43：Synthesize 5- (2- Thenoyls) -8- (trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,2-a]
Quinoline (compound 43)
1- (the 4- chlorine in embodiment 2 is replaced with 2- (tetrahydropyrimidine -2 (1H)-subunit) -1- (thiophene -2- bases) second -1- ketone
Phenyl) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carry out reaction white solid 5- (2- Thenoyls) -8- can be obtained
(trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (compound 43), yield 92%.Fusing point：209~210 DEG C.
High resolution mass spectrum C18H14F3N2OS[M+H]+, theoretical value 363.0773；Measured value, 363.0777.
Embodiment 44：Synthesize 4- (4- fluoro benzoyls) -7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline
(compound 44)
1- (4- chlorphenyls) -2- in embodiment 3 is replaced with 1- (4- fluorophenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carries out reaction and yellow solid 4- (4- fluoro benzoyls) -7- (fluoroforms can be obtained
Base) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 44), yield 95%.Fusing point：194~195 DEG C.
High resolution mass spectrum C19H13F4N2O[M+H]+, theoretical value 361.0959；Measured value, 361.0958.
Embodiment 45：Synthesize 4- (4- chlorobenzene formacyls) -7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline
(compound 45)
1- (4- chlorphenyls) -2- in embodiment 3 is replaced with 1- (4- chlorphenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carries out reaction and yellow solid 4- (4- chlorobenzene formacyls) -7- (fluoroforms can be obtained
Base) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 45), yield 97%.Fusing point：232~233 DEG C.
High resolution mass spectrum C19H13ClF3N2O[M+H]+, theoretical value 377.0663；Measured value 377.0664.
Embodiment 46：Synthesize 4- (4- benzoyl bromides) -7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline
(compound 46)
1- (4- chlorphenyls) -2- in embodiment 3 is replaced with 1- (4- bromophenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carries out reaction and yellow solid 4- (4- benzoyl bromides) -7- (fluoroforms can be obtained
Base) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 46), yield 97%.Fusing point：237~238 DEG C.
High resolution mass spectrum C19H13BrF3N2O[M+H]+, theoretical value 421.0158；Measured value 421.0158.
Embodiment 47：Synthesize 4- benzoyls -7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (chemical combination
Object 47)
1- (4- chlorphenyls) -2- (four in embodiment 3 is replaced with 2- (imidazolidine -2- subunits) -1- diphenylphosphino ethane -1- ketone
Hydrogen pyrimidine -2 (1H)-subunit) second -1- ketone carry out reaction yellow solid 4- benzoyls -7- (trifluoromethyl) -1,2- two can be obtained
Hydrogen-imidazo [1,2-a] quinoline (compound 47), yield 95%.Fusing point：212~213 DEG C.
High resolution mass spectrum C19H14F3N2O[M+H]+, theoretical value 343.1053；Measured value, 343.1050.
Embodiment 48：4- is synthesized to toluyl groups -7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline
(compound 48)
1- (4- chlorphenyls) -2- in embodiment 3 is replaced with 2- (imidazolidine -2- subunits) -1- (p-methylphenyl) second -1- ketone
(tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carries out reaction and yellow solid 4- can be obtained to toluyl groups -7- (fluoroforms
Base) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 48), yield 92%.Fusing point：249~250 DEG C.
High resolution mass spectrum C20H16F3N2O[M+H]+, theoretical value 357.1209；Measured value, 357.1210.
Embodiment 49：Synthesize 4- (4- methoxybenzoyls base) -7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a]
Quinoline (compound 49)
1- (the 4- chlorobenzenes in embodiment 3 are replaced with 2- (imidazolidine -2- subunits) -1- (4- methoxyphenyls) second -1- ketone
Base) -2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carry out reaction yellow solid 4- (4- methoxybenzoyls base)-can be obtained
7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 49), yield 92%.Fusing point：228~229 DEG C.Its
Mono-crystalline structures are as shown in Figure 1.
High resolution mass spectrum C20H16F3N2O2[M+H]+, theoretical value 373.1158；Measured value, 373.1160.
Embodiment 50：Synthesize 4- (2- Thenoyls) -7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline
(compound 50)
The 1- (4- chlorphenyls)-in embodiment 3 is replaced with 2- (imidazolidine -2- subunits) -1- (thiophene -2- bases) second -1- ketone
2- (tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carries out reaction and orange solids 4- (2- Thenoyls) -7- (trifluoros can be obtained
Methyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 50), yield 93%.Fusing point：208~209 DEG C.
High resolution mass spectrum C17H12F3N2OS[M+H]+, theoretical value 349.0617；Measured value 349.0614.
Embodiment 51：Synthesize 4- (2- chlorobenzene formacyls) -7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline
(compound 51)
1- (4- chlorphenyls) -2- in embodiment 3 is replaced with 1- (2- chlorphenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(tetrahydropyrimidine -2 (1H)-subunit) second -1- ketone carries out reaction and red solid 4- (2- chlorobenzene formacyls) -7- (fluoroforms can be obtained
Base) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 51), yield 95%.Fusing point：223~224 DEG C.
High resolution mass spectrum C19H13ClF3N2O[M+H]+, theoretical value 377.0665；Measured value 377.0665.
Simultaneously [1,2-a] quinolines, structure are as shown in table 1 for above synthesized 1, the 3- diazacyclos.
The structural formula of 1. 1,3- diazacyclos of table simultaneously [1,2-a] quinolines
The antitumous effect of second part the compounds of this invention
Application examples
51 compounds of the present invention tested for three-type-person's class tumor cell line：HCT116 (people's Colon and rectums
Cancer), A549 (lung cancer), HT29 (colon cancer), SGC7901 (gastric cancer), HepG2 (liver cancer).By cell tests compound incubation
144 hours, then MTT measuring methods is used to measure cytotoxicity (Mossman, T.J.Immunol.Methods 1983,65,55
" the quick colorimetric test of cell viability；Cytotoxicity and the quantitative application of growth inhibition lymphokine ".Green,
" the quick colorimetric tests of cell viability of L.M.J.Immunol.Methods 1984,70,257；Cytotoxicity and growth inhibition
The quantitative application of lymphokine "), the results are shown in Table 2.
The data obtained confirms that the compound of the present invention is to entity tumor such as people's knot-carcinoma of the rectum (HCT116), human lung cancer
(A549), human colon carcinoma (HT29), human gastric cancer (SGC7901), human liver cancer (HepG2) preferable antitumor activity.Wherein, chemical combination
The IC of 2,17~28 pairs of people's knots of the object-carcinoma of the rectum (HCT116) cell strain50(μ g/mL) is respectively 4.75,4.06,6.35,5.00,
4.48,5.06,5.32,6.38,7.70,8.44,5.65,8.53,8.72, the respectively less than IC of positive control medicine cis-platinum50(μg/
ML)=8.74, and both less than 10 μ g/mL, superior active anticancer is shown relative to cis-platinum.Compound 17 and compound 21 are right
HCT116 (the people's knot-carcinoma of the rectum), A549 (lung cancer), HT29 (colon cancer), SGC7901 (gastric cancer), HepG2 (liver cancer) cell strain are equal
All show superior active anticancer, IC50Value is much smaller than the IC of positive control medicine cis-platinum50(μ g/mL) value, and both less than
10μg/mL。
It can be seen that according to data in table 2, for formula of the present invention (I) structural compounds, when the n in formula (I) is 2 Hes
When 3, IC50Value be significantly less than n be 1 when, illustrate therewith to enhance with the increase of n, active anticancer.In addition, when in formula (I)
When Ar refers to the phenyl replaced for electron-withdrawing group, IC50The Ar that value is significantly less than in formula (I) refers to the benzene replaced for electron donating group
Base.The substitution for illustrating electron-withdrawing group is conducive to active enhancing.Compound 17 in embodiment 17, n=2 and Ar refer to inhale
The phenyl of electron group substitution, to HCT116 (the people's knot-carcinoma of the rectum), A549 (lung cancer), HT29 (colon cancer), SGC7901 (stomaches
Cancer), HepG2 (liver cancer) cell strain all shows superior active anticancer.IC50Value is much smaller than control group cis-platinum.
Cytotoxic activity of 2 the compounds of this invention of table to human tumor cell line
Note：IC in table50Value unit is μ g/mL；"-" expression is not surveyed.
The basic principles, main features and advantages of the present invention have been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (8)
1.1,3- diazacyclos simultaneously [1,2-a] quinolines, which is characterized in that the structure of the compound such as formula（Ⅰ）It is shown：
Wherein, formula（Ⅰ）In, Ar refers to phenyl or halogenophenyl；
R1~R4For halogen atom, hydrogen atom, nitro or piperidyl；
N is 1 or 2 or 3.
2. 1,3- diazacyclos described in claim 1 simultaneously [1,2-a] quinolines preparation method, which is characterized in that
Include the following steps：
Use formula（Ⅱ）The 2- fluorobenzaldehyde class compounds and formula of structure（Ⅲ）The heterocycle ketene peptide amine compound of structure is in solvent
In, it is heated under alkaline condition or inorganic salts existence condition, carrying out nucleophilic displacement of fluorine and condensation reaction, the reaction was complete to TLC detections
Afterwards, it purifies to get to formula（Ⅰ）Shown in 1,3- diazacyclos simultaneously [1,2-a] quinolines；
In formula（Ⅱ）In, R1~R4For halogen atom, hydrogen atom, nitro or piperidyl；
In formula（Ⅲ）In, Ar refers to phenyl or halogenophenyl；N is 1 or 2 or 3.
3. 1,3- diazacyclos according to claim 2 simultaneously [1,2-a] quinolines preparation method, feature exists
In, the solvent be methanol, ethyl alcohol, water, acetone, dichloromethane, chloroform, ethyl acetate,N,NDimethylformamide, tetrahydrochysene
The mixed solvent of one or more of furans, toluene, 1,4- dioxane and acetonitrile solvent.
4. 1,3- diazacyclos according to claim 2 simultaneously [1,2-a] quinolines preparation method, feature exists
In the alkali is the mixture of one or more of piperidines, triethylamine and calcium oxide, alkali and formula（Ⅲ）The heterocycle alkene of structure
The molar ratio of ketone contracting aminated compounds is 1：0.5~2；The inorganic salts are calcium chloride, inorganic salts and formula（Ⅲ）Structure it is miscellaneous
The molar ratio of annulenones contracting aminated compounds is 1：0.5~2.
5. 1,3- diazacyclos according to claim 2 simultaneously [1,2-a] quinolines preparation method, feature exists
In heating temperature is 40 ~ 110 DEG C.
6. 1,3- diazacyclos according to claim 2 simultaneously [1,2-a] quinolines preparation method, feature exists
In the reaction time is 0.5 ~ 24 hour.
7. 1,3- diazacyclos according to claim 2 simultaneously [1,2-a] quinolines preparation method, feature exists
In formula（Ⅱ）The 2- fluorobenzaldehyde class compounds and formula of structure（Ⅲ）The molar ratio of the heterocycle ketene peptide amine compound of structure is
1：1~3.
8. 1,3- diazacyclos described in claim 1 simultaneously [1,2-a] quinolines are as preparing answering for antitumor drug
With.
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| US20160257678A1 (en) * | 2015-03-04 | 2016-09-08 | Pimera, Inc. | Novel compositions, uses and methods for making them |
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| Regioselective construction of 1,3-diazaheterocycle fused [1,2-a][1,8]naphthyridine derivatives via cascade reaction of quinolines with heterocyclic ketene aminals： a joint experimental-computational approach;Yi-Chuan Zhang等;《Org.Biomol.Chem》;20131231;第11卷;第7276-7288页 * |
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