CN108003153A - Nitrogenous five-ring heterocycles and quinolines and its salt, preparation method, pharmaceutical composition and purposes - Google Patents
Nitrogenous five-ring heterocycles and quinolines and its salt, preparation method, pharmaceutical composition and purposes Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The present invention relates to nitrogenous five-ring heterocycles and quinolines and its salt, preparation method, pharmaceutical composition and purposes.Shown in the structural formula as I of the nitrogenous five-ring heterocycles and quinolines：
Description
It is the preferential of the Chinese patent application CN201711190023.3 on November 24th, 2017 this application claims the applying date
Power.Above-mentioned Chinese patent application is introduced into the application in the form of full text.
Technical field
The invention belongs to medicinal chemistry arts, and in particular to nitrogenous five-ring heterocycles and quinolines and its salt, preparation method,
Pharmaceutical composition and purposes.
Background technology
Alopecia is a kind of common skin disease, Mayo Clin Proc (IF=5.71) reports, alopecia areata almost with psoriasis
(being commonly called as psoriasis) is equally universal.Alopecia is also the common adverse effect after Chemotherapy on Patient with Tumor, and hair losing by chemical therapy is as alopecia areata
It is the impacted hair loss disorders of hair follicle, after 1-2 weeks alopecia can occur for general medication, its incidence is only second to Nausea and vomiting, change
(the Chemotherapy-induced alopecia of alopecia caused by treatment:CIA the psychological bad of anticancer therapy most serious can) be caused
Reaction.In the U.S., about 85% patients undergoing chemotherapy can undergo different degrees of alopecia.The female cancer patients of 47-85% are recognized
It is the external injury for the most serious that chemotherapy is brought for CIA, or even therefore the patient for having 8% refuses chemotherapy.After end of chemotherapy medication,
1-2 month hairs are renewable；A part of patient's alopecia can not recover completely；In most of patient, color and luster, the knot of hair are regenerated
Structure, quality and the speed of growth are all varied from, and the density of hair is also sparse compared with before chemotherapy.
The restorability of hair losing by chemical therapy depends on the degree that hair follicle stem cells are damaged.Alopecia caused by chemotherapy be mainly because
The hair follicle cutin mother cell of the differentiated in growth period has been significantly affected for chemotherapeutics.Such cell is located at hair lower end
Ball top position, if subjected to destroying can be supplemented by the hair follicle stem cells of sebaceous glands lower end.The knot that such a situation produces
Fruit is only temporarily coming off for hair.In the case of other chemotherapy, if hair follicle stem cells receive destruction completely, then lead
The alopecia of cause would is that irreversible.
It is applied to clinical medicine at present and method does not realize the purpose of effective hair growth also, and exists different degrees of
Side effect, such as side effect of the androgen receptor competitive inhibitor to male patient are womanlike, sexual hypoesthesia.To being at present
Only, in addition to topical hypothermia's (wearing ice cap) clinically has proven to have certain prevention CIA, other various methods are not in clinic
Upper confirmation has the effect of definite.
Therefore, the selectivity and validity that raising medicine breeds hair follicle are the emphasis and difficult point of hair growth research, are compeled
Be essential the compound that develop for hair follicle stem cells, reduces to toxic side effect caused by other target spots, associated to treat
Disease, the new selection of the offer such as alopecia, chemotherapy of tumors, hair follicles damage as caused by all kinds of reasons.
TLR7 (Toll-like receptor 7) is distributed more in hair follicle, has this special Dominance, with hair follicle stem cells
There are coexpression；TLR7 is co-expressed in mouse skin interfollicular epithelium (IFE) keratinocyte with stem cell and progenitor cells；TLR7
Hair follicle can be promoted to breed after receptor agonism.The small molecule TLR7 activators of existing report have Imiquimod, Gardiquimod,
Resiquimod, but there has been no the research for causing alopecia on treatment antitumor drug for these activators.Present inventor
The structure of existing a variety of small molecule TLR7 activators is studied, micromolecular compound has been carried out according to drug design principle
Structure design, and the hair follicle proliferation activity of the micromolecular compound of synthesis is screened.
The content of the invention
Nitrogenous five-ring heterocycles shown in the present invention provides general formula I and quinolines and its pharmaceutically acceptable
Salt：
Wherein：
R1Selected from hydrogen, halogen, hydroxyl, cyano group, amino, nitro, substituted or non-substituted C1-10It is alkyl, substituted or non-substituted
C2-10Alkenyl, substituted or non-substituted C2-10Alkynyl, substituted or non-substituted C1-10Alkoxy, substituted or non-substituted C1-10
Alkylthio group, substituted or non-substituted C3-10It is cycloalkyl, substituted or non-substituted aryl, substituted or non-substituted containing N's and/or O
3-8 unit's heteroaryls；
Wherein it is preferred to substituted C1-10Alkyl, the C of substitution1-10Alkoxy, the C of substitution1-10Alkylthio group, substitution
C2-10Alkenyl, the C of substitution2-10Alkynyl is optionally substituted by 1,2 or 3 identical or different substituent, and the substituent is selected from：Halogen
Element, hydroxyl, cyano group, amino, nitro；
Preferably, substituted C3-10Cycloalkyl is optionally substituted by 1,2 or 3 identical or different substituent, the substitution
Base is selected from：Halogen, hydroxyl, sulfydryl, carboxyl, nitro；
Preferably, substituted or non-substituted aryl is optionally substituted by 1,2 or 3 identical or different substituent, described to take
One or more of the Dai Ji in halogen, hydroxyl, nitro, amino, cyano group, sulfonic group or carboxyl, it is further preferred that aryl
It is phenyl, benzyl, naphthyl；
Preferably, the substituted or non-substituted 3-8 unit's heteroaryls selection of land containing N and/or O identical or different is taken by 1,2 or 3
Substitute for base, one or more of the substituent in halogen, hydroxyl, nitro, amino, cyano group, sulfonic group or carboxyl；
R2Selected from hydrogen, halogen, hydroxyl, cyano group, amino, nitro, substituted or non-substituted C1-10It is alkyl, substituted or non-substituted
C2-10Alkenyl, substituted or non-substituted C2-10Alkynyl, substituted or non-substituted C1-10Alkoxy, substituted or non-substituted C1-10
Alkylthio group, substituted or non-substituted C3-10It is cycloalkyl, substituted or non-substituted aryl, substituted or non-substituted containing N's and/or O
3-8 unit's heteroaryls；
Wherein it is preferred to substituted C1-10Alkyl, the C of substitution1-10Alkoxy, the C of substitution1-10Alkylthio group, substitution
C2-10Alkenyl, the C of substitution2-10Alkynyl is optionally substituted by 1,2 or 3 identical or different substituent, and the substituent is selected from：Halogen
Element, hydroxyl, cyano group, amino, nitro；
Preferably, substituted C3-10Cycloalkyl is optionally substituted by 1,2 or 3 identical or different substituent, the substitution
Base is selected from：Halogen, hydroxyl, sulfydryl, carboxyl, nitro；
Preferably, substituted or non-substituted aryl is optionally substituted by 1,2 or 3 identical or different substituent, described to take
One or more of the Dai Ji in halogen, hydroxyl, nitro, amino, cyano group, sulfonic group or carboxyl, it is further preferred that aryl
It is phenyl, benzyl, naphthyl；
Preferably, the substituted or non-substituted 3-8 unit's heteroaryls selection of land containing N and/or O identical or different is taken by 1,2 or 3
Substitute for base, one or more of the substituent in halogen, hydroxyl, nitro, amino, cyano group, sulfonic group or carboxyl；
N is 0,1,2,3；
A1、A2、A3N, C, O are separately selected from, and at least one is selected from N.
In another embodiment, the nitrogenous five-ring heterocycles shown in general formula I and quinolines and its pharmacy
Upper acceptable salt is general formula II-1, general formula II-2, general formula II-3, general formula II-4, general formula II-5, the chemical combination shown in general formula II-6
Thing：
In another embodiment, the nitrogenous five-ring heterocycles shown in general formula I and quinolines and its pharmacy
Upper acceptable salt is the compound as shown in following formula I -1：
In another embodiment, the nitrogenous five-ring heterocycles shown in general formula I and quinolines and its pharmacy
Upper acceptable salt, its pharmaceutically acceptable salt is inorganic salts and organic salt, selected from hydrochloride, hydrobromate, nitrate, phosphorus
Hydrochlorate, metaphosphate, sulfate, sulphite, perchlorate and formates, acetate, propionate, malonate, propylene
Hydrochlorate, succinate, oxalates, D or L malates, fumarate, maleate, benzoate, hydroxybutyric acid salt, adjacent benzene
Diformate, mesylate, esilate, sulfonate, salicylate, tartrate, citrate, lactate, mandelate,
One or more in butanedioic acid.
The preparation method of nitrogenous five-ring heterocycles and quinolines shown in present invention also offers general formula I, including nitre
Change, halogenation, amination, reduction, cyclization, including：
Step 1, using the 4- hydroxyquinoline compounds of Formula IV as starting material, acid is added, nitrating agent is then added and carries out
Nitration reaction, obtains the 4- hydroxyl -3- nitroquinoline compounds of Formula V, and reaction equation is as follows：
Step 2, the 4- hydroxyl -3- nitroquinoline compounds of Formula V are dissolved in solvent 1, add halogenating agent, reaction obtains formula
The chloro- 3- nitroquinolines compounds of 4- of IV, reaction equation are as follows：
Step 3, the chloro- 3- nitroquinolines compounds of the 4- of formula IV are dissolved in solvent 2, add alkali and aminated compounds carries out
Aminating reaction, obtains the 4- amino -3- nitroquinoline compounds of formula III, and reaction equation is as follows：
Step 4, the 4- amino -3- nitroquinoline compounds of formula III are dissolved in solvent 3, then add reducing agent and carry out
Reaction, obtains the 4- amino -3- aminoquinoline compounds of Formula II, reaction equation is as follows：
Step 5, hydrochloric acid and solvent 4 are added in the 4- amino -3- aminoquinoline compounds of Formula II, then add nitrous
Sour sodium carries out cyclization, and adjustment reaction solution is alkalescence, and gained sediment is the nitrogenous five-ring heterocycles and quinolines chemical combination of Formulas I
Thing, reaction equation are as follows：
One or more of the acid in formic acid, acetic acid, propionic acid, butyric acid, nitric acid described in above-mentioned steps 1；
And/or nitrating agent described in step 1 is in nitric acid, the concentrated sulfuric acid and nitrate mixture, acetyl group nitrate
One or more；Preferably, the one kind of the nitrate in sodium nitrate, potassium nitrate；
And/or halogenating agent described in step 2 is selected from phosphorus pentahalides, phosphorus oxychloride, oxalyl chloride, triphenyl phosphorus dichloride
(Ph3PCl2), phosphorus pentabromide, phosphorus oxybromide, the one or more in triphenyl dibrominated phosphorus；
And/or alkali described in step 3 is selected from triethylamine, trimethylamine, sodium carbonate (Na2CO3), sodium acid carbonate (NaHCO3)、
Cesium carbonate (Cs2CO3), potassium carbonate (K2CO3), the one or more in pyridine；
And/or aminated compounds described in step 3 is selected from monoethanolamine, Propanolamine, isopropanolamine, butanolamine or propargylamine；
And/or reducing agent described in step 4 is selected from iron powder, stannous chloride, tin, vulcanized sodium, sodium hydrosulfite (dithionic acid
Sodium), sulphite, hydrogen, palladium carbon, Raney's nickel (Raney Ni), Lithium Aluminium Hydride, sodium borohydride, thio sodium borohydride, one oxidation
One or more in carbon；
And/or the solvent 1, solvent 2, solvent 3 and solvent 4 are selected from water, methanol, ethanol, glycerine, dichloromethane, third
One or more in ketone, ethyl acetate, dioxane, toluene, dimethylbenzene, DMSO, DMF, tetrahydrofuran.
Present invention also offers pharmaceutical composition, and it includes the nitrogenous five-ring heterocycles and quinolines and its medicine of Formulas I
Acceptable salt on.
In another embodiment, described pharmaceutical composition further comprises one or more pharmaceutically acceptable figurations
Agent.
It is the optional Autoadhesive of the excipient, lubricant, glidant, disintegrant, granulating agent, coating agent, wetting agent, molten
One or more in agent, suspending agent, flavor enhancement.
In another embodiment, described pharmaceutical composition can oral administration, parenteral, suction spraying
Administration, rectally, intranasal administration, sublingual administration, cheek interior administration, cutaneous penetration or drug delivery implant.
In another embodiment, described pharmaceutical composition, which can be made into, is suitable for by required method of administration to suffering from
Person administration formulation, such as injection, capsule, tablet, pulvis, granule, lozenge, syrup, suspending agent, solution, emulsion,
Suppository.
The medicine group of nitrogenous five-ring heterocycles comprising formula I and quinolines and its pharmaceutically acceptable salt
Compound can use the method for medical domain routine be prepared, and wherein the content of active ingredient is the weight of 0.1 weight %~99.5
% is measured, this depends on to be treated or prevention illness and the characteristic for the subject for giving the compound.For giving
The dosage of compound can be readily determined by those skilled in the art using disclosure herein.
In another embodiment, the nitrogenous five-ring heterocycles of Formulas I and quinolines and its can pharmaceutically connect
The salt received can be combined with other one or more active medicine components.The combination medicine can be comprising the compounds of this invention or its
The form of pharmaceutically acceptable salt and the composition of one or more other active medicines combinations point.
Present invention also offers Formulas I nitrogenous five-ring heterocycles and quinolines and its pharmaceutically acceptable salt or its
Pharmaceutical composition is used to prepare the purposes of the medicine with hair follicle proliferation function.
Present invention also offers Formulas I nitrogenous five-ring heterocycles and quinolines and its pharmaceutically acceptable salt or its
Pharmaceutical composition be used to prepare treatment common baldness, chemicotherapy alopecia, hair follicles damage medicine purposes.
The nitrogenous five-ring heterocycles and quinolines of Formulas I provided by the invention have the function that to promote hair follicle propagation.Can
Cream is made in the nitrogenous five-ring heterocycles of the present invention and quinolines, locally uses in scalp, on the one hand can promote
Hair follicle is bred, and on the other hand the influence to oncotherapy is less.
Brief description of the drawings
Fig. 1 is to apply mouse hair follicles section HE stain controls figure (first) after drug containing cream and pure emulsifiable paste matrix.
Fig. 2 is mouse hair follicles section HE stain controls figure (second) after drug containing cream and pure emulsifiable paste matrix.
Fig. 3 is mouse hair follicles section HE stain controls figure (the 3rd) after drug containing cream and pure emulsifiable paste matrix.
Fig. 4 is mouse hair follicles section HE stain controls figure (the 4th) after drug containing cream and not dispenser.
Fig. 5 is mouse hair follicles section HE stain controls figure (the 5th) after drug containing cream and pure emulsifiable paste matrix.
Embodiment
The embodiment of the present invention is described in detail below, it is to be understood that protection scope of the present invention is not
Limited by embodiment.
Embodiment 1：The synthesis of 1- ethoxys -1H- [1,2,3] triazole [4,5-c] quinoline
The first step：
Second step：
3rd step：
4th step：
5th step：
The first step：The 4- oxyquinolines (34.48mmol, is purchased from nine ancient cooking vessels chemistry) of the Formula IV -1 of 5g are dissolved in propionic acid
(40mL, purity >=99.5%) is heated to 120 DEG C；Then, by the concentrated nitric acid of the 3.5mL after being diluted with propionic acid (41.38mmol,
Concentration is concentrated nitric acid 65-68%) slowly instilled in 1.5h, after about 15min, there is yellow mercury oxide generation；Add propionic acid 20mL after
Continuous reflux 1h, TLC (thin-layer chromatography) display has no reactant 4- oxyquinolines, stops heating, cooling reaction solution to room temperature；Filtering
Reaction solution, filter cake petroleum ether, vacuum drying, gained yellow solid is the 4- hydroxyl -3- nitroquinolines of Formula V -1
(5.28g, average yield 80.7%), fusing point>300℃.
1HNMR(DMSO-d6,400MHz):σ (ppm) 13.01 (br, 1H), 9.20 (d, 1H, J=6Hz), 8.27 (d, 1H, J
=7.6Hz), 7.81 (td, 1H, J1=7.6Hz, J2=1.4Hz), 7.73 (d, 1H, J=7.6Hz) 7.53 (t, 1H, J=
7.6Hz).IR(KBr):3445,3161,3099,1618,1561,1438,1383,1340,1197,844,765 cm-1.MS
(ES-)m/z:189(M-H+).HRMS m/s calculated for C9H6N2O3+Na+213.0271,found 213.0276.
Second step：4- hydroxyl -3- the nitroquinolines (2g, 10.53mmol) of Formula V -1 are dissolved in dichloromethane, then
Oxalyl chloride (4.5mL, 52.65mmol) is slowly dropped into, after bubble formation relaxes, is heated to 40 DEG C；Reaction is concentrated after half an hour
Liquid, the chloro- 3- nitroquinolines of 4- of gained white solid, that is, Formula IV -1, fusing point are 116~118 DEG C.
1HNMR(DMSO-d6,400MHz):σ (ppm) 9.15 (d, 1H, J=7.2Hz), 8.25 (d, 1H, J=8Hz), 7.79
(d, 2H, J=2.4Hz), 7.54-7.50 (m, 1H) .IR (KBr):3166,3100,1621,1599,1562,1443,1340,
845,764cm-1.MS(ES-)m/z:207(M-H+)HRMS m/s calculated for C9H5ClN2O2-H+206.9967,
found 206.9960.
3rd step：The chloro- 3- nitroquinolines (1.37g, 6.59mmol) of the 4- of Formula IV -1 are dissolved in the methanol of 20ml, ice
Water cooling；Then, triethylamine 1.4ml (>=98%) and monoethanolamine 0.6ml (>=99%) is added, reaction solution is stirred overnight, next day
Filtering, obtained solid is 3- nitros -4- hydroxyethylaminos-quinoline (1.16g, the two step average yields of formula III -1：
75.7%), fusing point is 184~186 DEG C.
1HNMR(CDCl3,400MHz):σ (ppm) 9.89 (br, 1H), 9.38 (s, 1H), 8.31 (d, 1H, J=8.4Hz),
8.03 (d, 1H, J=8.4Hz), 7.78 (t, 1H, J=7.6Hz), 7.50 (t, 1H, J=7.4Hz), 4.13 (quant, 2H, J=
5.2Hz), 4.0 (t, 2H, J=5.2Hz) .IR (KBr):3293,3159,1615,1593,1564,1536,1471,1417,
1394,1337,1250,1200,1059,760cm-1.MS(EI+)m/z:234(M+H+).HRMS m/s calculated for
C11H11N3O3+H+234.0873,found 234.0873.
4th step：The compound 4 (1g, 4.29mmol) of formula III -1 is dissolved in isopropanol and is heated to 100 DEG C；So
Afterwards, the aqueous solution (sodium hydrosulfite 7.5g, water 50ml) of sodium hydrosulfite (sodium dithionate) is instilled, allows at 100 DEG C of reaction solution and stirs 0.5h；
When TLC shows reactionless thing, stopping heating, separates supernatant liquid, concentration of reaction solution；Solid after concentration is extracted with ethanol, dense
Contracting ethanol up to brown oil, i.e. Formula II -1 3- amino -4- hydroxyethylaminos-quinoline (896mg, average yield：
34.7%).
1HNMR(CDCl3,400MHz):σ(ppm)8.42(s,1H),7.98-7.95(m,2H),7.52-7.39(m,2H),
3.92 (br, 3H), 3.73 (t, 2H, J=4.4Hz), 3.44 (t, 2H, J=4.4Hz), 1.26 (s, 1H) .IR (KBr):3331,
3216,2963,2852,1617,1571,1466,1439,1347,1261,799cm-1.MS(ES+)m/z:204(M+H+)
.HRMS m/s calculated for C11H13N3O+H+204.1131,found 204.1136.
5th step：By the compound 5 (1.634g, 8.04mmol) of Formula II -1, hydrochloric acid 1.5ml (12mol/l), ethanol
10ml, water 10ml, are placed in single neck bottle and are cooled to 0 DEG C；Then, sodium nitrite 833mg is added by several times, and reaction solution is stirred overnight；
Next day, filtering reacting liquid, with NaOH quaternizations liquid to pH ≈ 12, the precipitation of gained be the 1- ethoxys -1H- of Formulas I -1 [1,
2,3] triazole [4,5-c] quinoline product；If without precipitation, after being extracted with ethyl acetate, purified with the method for column chromatography,
(806mg, average yield：48.3%), fusing point is 170~172 DEG C.
1HNMR(CDCl3,400MHz):σ(ppm)9.44(s,1H),8.42(dd,1H,J1=8.4Hz, J2=0.8Hz),
8.27 (d, 1H, J=8.4Hz), 7.83 (td, 1H, J1=7.6Hz, J2=1.2Hz), 7.50 (td, 1H, J1=7.8Hz, J2=
1.2Hz), 5.17 (t, 2H, J=5.2Hz), 4.45 (t, 2H, J=5Hz) .IR (KBr):3292,3070,3007,2941,
2851,1621,1586,1524,1454,1388,1323,1166,1069,761cm-1.MS(EI+)m/z:237(M+Na+)
.HRMS m/s calculated for C11H10N4O+Na+237.0747,found 237.0745.
Biological examples
Experimental subjects：6 week old C57 male mices, are divided into A groups and B groups, and wherein A groups are made to application of containing embodiment 1
1- ethoxys -1H- [1,2,3] triazole [4,5-c] quinoline cream, B groups are only to application of the control of cream auxiliary material
Group, every group of mouse choose 5 and are only used as experimental subjects.
Cream accessory formula：It is glycerin monostearate 0.8g, stearic acid 0.8g, albolene 2g, atoleine 8g, sweet
Oily 10g, water 16g, lauryl sodium sulfate 0.4g, borneol 0.2g, dimethyl sulfoxide 1.8g.Main ingredient：1- hydroxyls second made from embodiment 1
The content of base -1H- [1,2,3] triazole [4,5-c] quinoline is the above-mentioned matrix of 10mg/10ml.
All raw materials are placed in 80 DEG C of water-baths, 30min is stirred clockwise, is cooled to room temperature.
Operating process：After C57 mouse are anaesthetized with ethobrom, the paraffin of fusing is spread at back；Torn after paraffin
Back hair is removed, exposes skin；The 9th day after epilation, endoxan (20 μ g/g) is injected；Since being administered the same day, carried on the back in mouse
Portion's skin smears medicine 1 time/2 days；The 40 pure emulsifiable paste matrixes of μ l are smeared in left side, and 40 μ l of drug containing emulsifiable paste are smeared on right side；Put to death mouse within 21st day,
Back is drawn materials, section, HE dyeing, mounting.
Experimental result is as follows：Contrast A groups and B group hair follicle quantity under equal high power or low-power field.Mouse back skin hair
Capsule is coloured to blueness, and in figure under equal area, blue dot A groups are more obvious than B groups more, show to give and made containing embodiment 1
There is obvious promotion hair follicle propagation after the cream of 1- ethoxys -1H- [1,2,3] triazole [4,5-c] quinoline obtained to mouse
Effect is (referring to Fig. 1~Fig. 5), and improve significantly common baldness, chemicotherapy alopecia, hair follicles damage effect.
It is foregoing to the present invention specific exemplary embodiment description be in order to illustrate and illustration purpose.These descriptions
It is not wishing to limit the invention to disclosed precise forms, and it will be apparent that according to the above instruction, can be much changed
And change.The purpose of selecting and describing the exemplary embodiment is that explain that the certain principles of the present invention and its reality should
With so that those skilled in the art can realize and utilize the present invention a variety of exemplaries and
Various chooses and changes.The scope of the present invention is intended to be limited by claims and its equivalents.
Claims (10)
1. nitrogenous five-ring heterocycles and quinolines and its pharmaceutically acceptable salt shown in general formula I：
Wherein：
R1Selected from hydrogen, halogen, hydroxyl, cyano group, amino, nitro, substituted or non-substituted C1-10It is alkyl, substituted or non-substituted
C2-10Alkenyl, substituted or non-substituted C2-10Alkynyl, substituted or non-substituted C1-10Alkoxy, substituted or non-substituted C1-10Alkane
Sulfenyl, substituted or non-substituted C3-10Cycloalkyl, substituted or non-substituted aryl, the substituted or non-substituted 3-8 containing N and/or O
Unit's heteroaryl；
R2Selected from hydrogen, halogen, hydroxyl, cyano group, amino, nitro, substituted or non-substituted C1-10It is alkyl, substituted or non-substituted
C2-10Alkenyl, substituted or non-substituted C2-10Alkynyl, substituted or non-substituted C1-10Alkoxy, substituted or non-substituted C1-10Alkane
Sulfenyl, substituted or non-substituted C3-10Cycloalkyl, substituted or non-substituted aryl, the substituted or non-substituted 3-8 containing N and/or O
Unit's heteroaryl；
N is 0,1,2,3；
A1、A2、A3N, C, O are separately selected from, and at least one is selected from N；
Wherein, the R1And R2In：
Preferably, substituted C1-10Alkyl, the C of substitution1-10Alkoxy, the C of substitution1-10Alkylthio group, the C of substitution2-10Alkenyl, substitution
C2-10Alkynyl is optionally substituted by 1,2 or 3 identical or different substituent, and the substituent is selected from：Halogen, hydroxyl, cyano group,
Amino, nitro；
Preferably, substituted C3-10Cycloalkyl is optionally substituted by 1,2 or 3 identical or different substituent, the substituent choosing
From：Halogen, hydroxyl, sulfydryl, carboxyl, nitro；
Preferably, substituted or non-substituted aryl is optionally substituted by 1,2 or 3 identical or different substituent, the substituent
One or more in halogen, hydroxyl, nitro, amino, cyano group, sulfonic group or carboxyl, it is further preferred that aryl is benzene
Base, benzyl, naphthyl；
Preferably, the substituted or non-substituted 3-8 unit's heteroaryls selection of land containing N and/or O is by 1,2 or 3 identical or different substituent
Substitution, one or more of the substituent in halogen, hydroxyl, nitro, amino, cyano group, sulfonic group or carboxyl.
2. nitrogenous five-ring heterocycles according to claim 1 and quinolines and its pharmaceutically acceptable salt, it is
General formula II-1, general formula II-2, general formula II-3, general formula II-4, general formula II-5, the compound shown in general formula II-6：
3. nitrogenous five-ring heterocycles according to claim 2 and quinolines and its pharmaceutically acceptable salt, it is special
Sign is that simultaneously quinolines are the structural compounds of following formula I -1 to the nitrogenous five-ring heterocycles：
4. nitrogenous five-ring heterocycles according to claim 1 and quinolines and its pharmaceutically acceptable salt, it is special
Sign is：The pharmaceutically acceptable salt is inorganic salts and organic salt, selected from hydrochloride, hydrobromate, nitrate, phosphoric acid
Salt, metaphosphate, sulfate, sulphite, perchlorate and formates, acetate, propionate, malonate, acrylic acid
Salt, succinate, oxalates, D or L malates, fumarate, maleate, benzoate, hydroxybutyric acid salt, adjacent benzene two
Formates, mesylate, esilate, sulfonate, salicylate, tartrate, citrate, lactate, mandelate, amber
One or more in amber acid.
5. the preparation method of the nitrogenous five-ring heterocycles and quinolines described in claim 1-4 any one, including：
Step 1, using the 4- hydroxyquinoline compounds of Formula IV as starting material, acid is added, nitrating agent is then added and is nitrified
Reaction, obtains the 4- hydroxyl -3- nitroquinoline compounds of Formula V, reaction equation is as follows：
Step 2, the 4- hydroxyl -3- nitroquinoline compounds of Formula V are dissolved in solvent 1, add halogenating agent, reaction obtains formula IV
The chloro- 3- nitroquinolines compounds of 4-, reaction equation are as follows：
Step 3, the chloro- 3- nitroquinolines compounds of the 4- of formula IV are dissolved in solvent 2, add alkali and aminated compounds carries out ammonification
Reaction, obtains the 4- amino -3- nitroquinoline compounds of formula III, reaction equation is as follows：
Step 4, the 4- amino -3- nitroquinoline compounds of formula III are dissolved in solvent 3, then add reducing agent and reacted,
4- amino -3- the aminoquinoline compounds of Formula II are obtained, reaction equation is as follows：
Step 5, hydrochloric acid and solvent 4 are added in the 4- amino -3- aminoquinoline compounds of Formula II, then add sodium nitrite
Cyclization is carried out, adjustment reaction solution is alkalescence, and gained sediment is the nitrogenous five-ring heterocycles and quinolines of Formulas I,
Reaction equation is as follows：
6. preparation method according to claim 5, it is characterised in that：
One or more of the acid described in step 1 in formic acid, acetic acid, propionic acid, butyric acid, nitric acid；
And/or nitrating agent described in step 1 in nitric acid, the concentrated sulfuric acid and nitrate mixture, acetyl group nitrate one
Kind is a variety of；Preferably, the one kind of the nitrate in sodium nitrate, potassium nitrate；
And/or halogenating agent described in step 2 is selected from phosphorus pentahalides, phosphorus oxychloride, oxalyl chloride, triphenyl phosphorus dichloride, five brominations
One or more in phosphorus, phosphorus oxybromide, triphenyl dibrominated phosphorus；
And/or alkali described in step 3 is in triethylamine, trimethylamine, sodium carbonate, sodium acid carbonate, cesium carbonate, potassium carbonate, pyridine
One or more；
And/or aminated compounds described in step 3 is selected from monoethanolamine, Propanolamine, isopropanolamine, butanolamine or propargylamine；
And/or reducing agent described in step 4 be selected from iron powder, stannous chloride, tin, vulcanized sodium, sodium hydrosulfite, sulphite, hydrogen,
One or more in palladium carbon, Raney's nickel, Lithium Aluminium Hydride, sodium borohydride, thio sodium borohydride, carbon monoxide；
And/or the solvent 1, solvent 2, solvent 3 and solvent 4 be selected from water, methanol, ethanol, glycerine, dichloromethane, acetone,
One or more in ethyl acetate, dioxane, toluene, dimethylbenzene, DMSO, DMF, ether, tetrahydrofuran.
7. pharmaceutical composition, it includes the nitrogenous five-ring heterocycles described in claim 1-4 any one and quinolines and
Its pharmaceutically acceptable salt.
8. pharmaceutical composition according to claim 7, it further comprises one or more pharmaceutically acceptable excipients.
9. nitrogenous five-ring heterocycles and quinolines and its pharmaceutically acceptable salt described in claim 1-4 any one
Or the pharmaceutical composition described in claim 7-8 any one is used to prepare the purposes of the medicine with hair follicle proliferation function.
10. nitrogenous five-ring heterocycles described in claim 1-4 any one and quinolines and its pharmaceutically acceptable
Pharmaceutical composition described in salt or claim 7-8 any one is used to prepare treatment common baldness, chemicotherapy alopecia, hair follicle damage
The purposes of the medicine of wound.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US11530218B2 (en) | 2020-01-20 | 2022-12-20 | Incyte Corporation | Spiro compounds as inhibitors of KRAS |
| US11739102B2 (en) | 2020-05-13 | 2023-08-29 | Incyte Corporation | Fused pyrimidine compounds as KRAS inhibitors |
| US11767320B2 (en) | 2020-10-02 | 2023-09-26 | Incyte Corporation | Bicyclic dione compounds as inhibitors of KRAS |
| US11939328B2 (en) | 2021-10-14 | 2024-03-26 | Incyte Corporation | Quinoline compounds as inhibitors of KRAS |
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| CN102399218A (en) * | 2010-09-16 | 2012-04-04 | 和记黄埔医药（上海）有限公司 | Triheterocyclic compounds and their use as PI3K inhibitors |
| US20150080381A1 (en) * | 2012-04-12 | 2015-03-19 | Ironwood Pharmaceuticals, Inc. | Methods of treating alopecia and acne |
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| CN102399218A (en) * | 2010-09-16 | 2012-04-04 | 和记黄埔医药（上海）有限公司 | Triheterocyclic compounds and their use as PI3K inhibitors |
| US20150080381A1 (en) * | 2012-04-12 | 2015-03-19 | Ironwood Pharmaceuticals, Inc. | Methods of treating alopecia and acne |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11530218B2 (en) | 2020-01-20 | 2022-12-20 | Incyte Corporation | Spiro compounds as inhibitors of KRAS |
| US11739102B2 (en) | 2020-05-13 | 2023-08-29 | Incyte Corporation | Fused pyrimidine compounds as KRAS inhibitors |
| US11767320B2 (en) | 2020-10-02 | 2023-09-26 | Incyte Corporation | Bicyclic dione compounds as inhibitors of KRAS |
| US11939328B2 (en) | 2021-10-14 | 2024-03-26 | Incyte Corporation | Quinoline compounds as inhibitors of KRAS |
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