CN108003153B - Nitrogen-containing five-membered heterocyclic quinoline compound and salt, preparation method, pharmaceutical composition and application thereof - Google Patents

Nitrogen-containing five-membered heterocyclic quinoline compound and salt, preparation method, pharmaceutical composition and application thereof Download PDF

Info

Publication number
CN108003153B
CN108003153B CN201711279295.0A CN201711279295A CN108003153B CN 108003153 B CN108003153 B CN 108003153B CN 201711279295 A CN201711279295 A CN 201711279295A CN 108003153 B CN108003153 B CN 108003153B
Authority
CN
China
Prior art keywords
nitrogen
membered heterocyclic
quinoline compound
pharmaceutically acceptable
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201711279295.0A
Other languages
Chinese (zh)
Other versions
CN108003153A (en
Inventor
杨谨成
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cancer Hospital and Institute of CAMS and PUMC
Original Assignee
Cancer Hospital and Institute of CAMS and PUMC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cancer Hospital and Institute of CAMS and PUMC filed Critical Cancer Hospital and Institute of CAMS and PUMC
Publication of CN108003153A publication Critical patent/CN108003153A/en
Application granted granted Critical
Publication of CN108003153B publication Critical patent/CN108003153B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • 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 invention relates to a nitrogen-containing five-membered heterocyclic quinoline compound and salts thereof, a preparation method, a pharmaceutical composition and application. The structural formula of the nitrogen-containing five-membered heterocyclic quinoline compound is shown as I:

Description

Nitrogen-containing five-membered heterocyclic quinoline compound and salt, preparation method, pharmaceutical composition and application thereof
The present application claims priority from chinese patent application CN201711190023.3 filed 24/11/2017. The above-mentioned chinese patent application is incorporated in its entirety into the present application.
Technical Field
The invention belongs to the field of medical chemistry, and particularly relates to a nitrogen-containing five-membered heterocyclic quinoline compound, a salt thereof, a preparation method, a pharmaceutical composition and application.
Background
Alopecia is a common skin disease, reported by Mayo Clin Proc (IF ═ 5.71), and alopecia areata is almost as common as psoriasis (commonly known as psoriasis). Alopecia is also a common side effect of tumor patients after Chemotherapy, Chemotherapy alopecia and alopecia areata are also hair loss diseases with affected hair follicles, generally, the alopecia can occur after 1-2 weeks of medication, the incidence rate is second to nausea and vomiting, and Chemotherapy-induced alopecia (CIA) can cause the most serious psychological adverse reaction of anti-cancer treatment. In the united states, approximately 85% of chemotherapy patients experience varying degrees of alopecia. 47-85% of female cancer patients consider CIA to be the most serious external injury from chemotherapy, and even 8% of patients reject chemotherapy accordingly. After the chemotherapy is finished, the hair can regenerate within 1-2 months; some patients fail to recover completely from alopecia; in most patients, the color, structure, texture and growth rate of the regrown hair are changed, and the density of the hair is less dense than before chemotherapy.
The recoverability of chemotherapy alopecia depends on the extent to which the hair follicle stem cells are damaged. Chemotherapy-induced alopecia is primarily due to the fact that chemotherapy drugs significantly affect well-differentiated hair follicle keratinocytes in the anagen phase. Such cells are located in the hair bulb at the lower end of the hair and, if damaged, can be replenished by the hair follicle stem cells at the lower end of the sebaceous gland. This produces only a temporary loss of hair. In other chemotherapy cases, if the hair follicle stem cells are completely destroyed, the resulting hair loss will be irreversible.
The current clinical drugs and methods do not achieve the purpose of effectively treating alopecia, and have side effects of different degrees, such as feminization, hyposexuality and the like of the androgen receptor competitive inhibitor to male patients. To date, no other methods have clinically proven to have a definite therapeutic effect, except that local hypothermia (wearing an ice cap) has clinically proven to have a certain effect of preventing CIA.
Therefore, the improvement of the selectivity and the effectiveness of the medicine on the hair follicle proliferation is a key and difficult point of the research on the hair loss treatment, and the development of a compound aiming at hair follicle stem cells is urgently needed, so that the toxic and side effects on other targets are reduced, and a new choice is provided for the treatment of related diseases, such as hair loss, tumor chemotherapy, hair follicle injury and the like caused by various reasons.
TLR7 (Toll-like receptor 7) is distributed in hair follicles more, has the special distribution advantage and is co-expressed with hair follicle stem cells; TLR7 is co-expressed with stem and progenitor cells in mouse epidermal interfollicular epithelium (IFE) keratinocytes; the TLR7 receptor can promote the proliferation of hair follicle after being excited. The small-molecule TLR7 agonists reported in the prior art include Imiquimod, Gardiquimod and Resiquimod, but the agonists have not been researched on treating alopecia caused by anti-tumor drugs. The inventor of the application researches the structures of various existing small molecule TLR7 agonists, designs the structure of a small molecule compound according to the drug design principle, and screens the hair follicle proliferation activity of the synthesized small molecule compound.
Disclosure of Invention
The invention provides a nitrogen-containing five-membered heterocyclic quinoline compound shown in a general formula I and pharmaceutically acceptable salts thereof:
Figure BDA0001497205360000021
wherein:
R1selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, substituted or unsubstituted C1-10Alkyl, substituted or unsubstituted C2-10Alkenyl, substituted or unsubstituted C2-10Alkynyl, substituted or unsubstituted C1-10Alkoxy, substituted or unsubstituted C1-10Alkylthio, substituted or unsubstituted C3-10Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted N and/or O containing 3-8 membered heteroaryl;
of these, preferably, substituted C1-10Alkyl, substituted C1-10Alkoxy, substituted C1-10Alkylthio, substituted C2-10Alkenyl, substituted C2-10Alkynyl is optionally substituted with 1,2 or 3 substituents which may be the same or different, selected from: halogen, hydroxy, cyano, amino, nitro;
preferably, substituted C3-10Cycloalkyl is optionally substituted with 1,2 or 3 substituents which may be the same or different, selected from: halogen, hydroxyl, sulfydryl, carboxyl and nitro;
preferably, the substituted or unsubstituted aryl group is optionally substituted with 1,2 or 3 same or different substituents selected from one or more of halogen, hydroxy, nitro, amino, cyano, sulfonic acid or carboxy, further preferably, the aryl group is phenyl, benzyl, naphthyl;
preferably, the substituted or unsubstituted N and/or O containing 3-8 membered heteroaryl is optionally substituted with 1,2 or 3 identical or different substituents selected from one or more of halogen, hydroxy, nitro, amino, cyano, sulfonic acid or carboxy;
R2selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, substituted or unsubstituted C1-10Alkyl, substituted or unsubstituted C2-10Alkenyl, substituted or unsubstituted C2-10Alkynyl, substituted or unsubstituted C1-10Alkoxy, substituted or unsubstituted C1-10Alkylthio, substituted or unsubstituted C3-10Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted N and/or O containing 3-8 membered heteroaryl;
among them, preferably, substituted C1-10Alkyl, substituted C1-10Alkoxy, substituted C1-10Alkylthio, substituted C2-10Alkenyl, substituted C2-10Alkynyl is optionally substituted with 1,2 or 3 substituents which may be the same or different, selected from: halogen, hydroxy, cyano, amino, nitro;
preferably, substituted C3-10Cycloalkyl is optionally substituted with 1,2 or 3 substituents which may be the same or different, selected from: halogen, hydroxyl, sulfydryl, carboxyl and nitro;
preferably, the substituted or unsubstituted aryl group is optionally substituted with 1,2 or 3 same or different substituents selected from one or more of halogen, hydroxy, nitro, amino, cyano, sulfonic acid or carboxy, further preferably, the aryl group is phenyl, benzyl, naphthyl;
preferably, the substituted or unsubstituted N and/or O containing 3-8 membered heteroaryl is optionally substituted with 1,2 or 3 identical or different substituents selected from one or more of halogen, hydroxy, nitro, amino, cyano, sulfonic acid or carboxy;
n is 0, 1,2, 3;
A1、A2、A3each independently selected from N, C, O, and at least one selected from N.
In another embodiment, the nitrogen-containing five-membered heterocyclic quinoline compound shown in the general formula I and the pharmaceutically acceptable salt thereof are compounds shown in the general formula II-1, the general formula II-2, the general formula II-3, the general formula II-4, the general formula II-5 and the general formula II-6:
Figure BDA0001497205360000031
in another embodiment, the nitrogen-containing five-membered heterocyclic quinoline compound shown in the general formula I and the pharmaceutically acceptable salt thereof are compounds shown in the following formula I-1:
Figure BDA0001497205360000041
in another embodiment, the nitrogen-containing five-membered heterocyclic quinoline compound shown in the general formula I and the pharmaceutically acceptable salts thereof are inorganic salts and organic salts, and are selected from hydrochloride, hydrobromide, nitrate, phosphate, metaphosphate, sulfate, sulfite, perchlorate, formate, acetate, propionate, malonate, acrylate, succinate, oxalate, D or L malate, fumarate, maleate, benzoate, hydroxybutyrate, phthalate, methanesulfonate, ethanesulfonate, sulfonate, salicylate, tartrate, citrate, lactate, mandelate and succinic acid.
The invention also provides a preparation method of the nitrogenous five-membered heterocyclic quinoline compound shown in the general formula I, which comprises the following reactions of nitration, halogenation, amination, reduction and cyclization:
step 1, taking a 4-hydroxyquinoline compound shown in a formula VI as a starting material, adding acid, and then adding a nitration reagent to carry out nitration reaction to obtain a 4-hydroxy-3-nitroquinoline compound shown in a formula V, wherein the reaction formula is as follows:
Figure BDA0001497205360000042
step 2, dissolving the 4-hydroxy-3-nitroquinoline compound shown in the formula V in a solvent 1, adding a halogenating agent, and reacting to obtain the 4-chloro-3-nitroquinoline compound shown in the formula IV, wherein the reaction formula is as follows:
Figure BDA0001497205360000043
and 3, dissolving the 4-chloro-3-nitroquinoline compound shown in the formula IV in a solvent 2, adding alkali and an amine compound to carry out an ammoniation reaction to obtain the 4-amino-3-nitroquinoline compound shown in the formula III, wherein the reaction formula is as follows:
Figure BDA0001497205360000051
step 4, dissolving the 4-amino-3-nitroquinoline compound shown in the formula III in a solvent 3, and then adding a reducing agent to react to obtain the 4-amino-3-aminoquinoline compound shown in the formula II, wherein the reaction formula is as follows:
Figure BDA0001497205360000052
step 5, adding hydrochloric acid and a solvent 4 into the 4-amino-3-aminoquinoline compound shown in the formula II, then adding sodium nitrite for cyclization reaction, adjusting the reaction liquid to be alkaline, and obtaining a precipitate which is the nitrogenous five-membered heterocyclic quinoline compound shown in the formula I, wherein the reaction formula is as follows:
Figure BDA0001497205360000053
the acid in the step 1 is selected from one or more of formic acid, acetic acid, propionic acid, butyric acid and nitric acid;
and/or, the nitrating reagent in the step 1 is one or more selected from nitric acid, concentrated sulfuric acid and nitrate mixture, and acetyl nitrate; preferably, the nitrate is selected from one of sodium nitrate and potassium nitrate;
and/or, in step 2, the halogenating agent is selected from phosphorus pentahalide, phosphorus oxychloride, oxalyl chloride, triphenyl phosphorus dichloride (Ph)3PCl2) One or more of phosphorus pentabromide, phosphorus oxybromide and triphenyl phosphorus dibromide;
and/or, in the step 3, the base is selected from triethylamine, trimethylamine and sodium carbonate (Na)2CO3) Sodium bicarbonate (NaHCO)3) Cesium carbonate (Cs)2CO3) Potassium carbonate (K)2CO3) One or more of pyridine;
and/or, in the step 3, the amine compound is selected from ethanolamine, propanolamine, isopropanolamine, butanolamine or propynylamine;
and/or, in the step 4, the reducing agent is selected from one or more of iron powder, stannous chloride, tin, sodium sulfide, sodium hydrosulfite (sodium dithionate), sulfite, hydrogen, palladium carbon, Raney nickel (Raney Ni), lithium aluminum hydride, sodium borohydride, and carbon monoxide;
and/or the solvent 1, the solvent 2, the solvent 3 and the solvent 4 are selected from one or more of water, methanol, ethanol, glycerol, dichloromethane, acetone, ethyl acetate, dioxane, toluene, xylene, DMSO, DMF and tetrahydrofuran.
The invention also provides a pharmaceutical composition which comprises the nitrogen-containing five-membered heterocyclic quinoline compound shown in the formula I and pharmaceutically acceptable salts thereof.
In another embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
The excipient can be selected from one or more of adhesive, lubricant, glidant, disintegrant, granulating agent, coating agent, wetting agent, solvent, suspending agent and flavoring agent.
In another embodiment, the pharmaceutical composition may be administered orally, parenterally, by inhalation spray, rectally, intranasally, sublingually, buccally, transdermally, or by implantation.
In another embodiment, the pharmaceutical composition can be formulated into a dosage form suitable for administration to a patient by a desired route of administration, such as injections, capsules, tablets, powders, granules, lozenges, syrups, suspensions, solutions, emulsions, suppositories.
Pharmaceutical compositions comprising the nitrogen-containing five-membered heterocyclic quinolines of formula I of the present invention and pharmaceutically acceptable salts thereof may be prepared by methods conventional in the medical field, wherein the content of the active ingredient is 0.1 to 99.5% by weight, depending on the condition to be treated or prevented and the characteristics of the subject to whom the compound is administered. Dosage regimens for a given compound can be readily determined by those skilled in the art using the disclosure herein.
In another embodiment, the nitrogen-containing five-membered heterocycloquinolines of formula I and pharmaceutically-acceptable salts thereof may be used in combination with one or more other active pharmaceutical ingredients. The combination may be in the form of a composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof and one or more other active pharmaceutical ingredients.
The invention also provides the application of the nitrogenous five-membered heterocyclic quinoline compound shown in the formula I and the pharmaceutically acceptable salt or the pharmaceutical composition thereof in preparing the medicine with the hair follicle proliferation effect.
The invention also provides the application of the nitrogenous five-membered heterocyclic quinoline compound shown in the formula I, and pharmaceutically acceptable salts or pharmaceutical compositions thereof in preparing medicines for treating alopecia universalis, alopecia caused by radiotherapy and chemotherapy and hair follicle injury.
The nitrogen-containing five-membered heterocyclic quinoline compound shown in the formula I has the effect of promoting hair follicle proliferation. The nitrogenous five-membered heterocyclic quinoline compound can be prepared into cream which is locally applied to the scalp, so that the cream can promote the hair follicle proliferation on one hand and has little influence on the tumor treatment on the other hand.
Drawings
FIG. 1 is a graph comparing HE staining of mouse hair follicle sections after application of the drug cream and pure cream matrix (first).
FIG. 2 is a graph comparing HE staining of hair follicle sections from mice after drug-containing cream and pure cream matrix (second).
FIG. 3 is a comparison graph of HE staining of mouse hair follicle sections after medicated cream and neat cream base (third).
FIG. 4 is a graph comparing HE staining of hair follicle sections from mice (fourth) with drug-containing creams and without drug administration.
FIG. 5 is a graph comparing HE staining of hair follicle sections in mice after the drug-containing cream and pure cream matrices (fifth).
Detailed Description
The following detailed description of specific embodiments of the invention is provided, but it should be understood that the scope of the invention is not limited to the specific embodiments.
Example 1: synthesis of 1-hydroxyethyl-1H- [1,2,3] triazole [4,5-c ] quinoline
The first step is as follows:
Figure BDA0001497205360000081
the second step is that:
Figure BDA0001497205360000082
the third step:
Figure BDA0001497205360000083
the fourth step:
Figure BDA0001497205360000084
the fifth step:
Figure BDA0001497205360000085
the first step is as follows: 5g of 4-hydroxyquinoline of the formula VI-1 (34.48mmol, from Jiuding chemical) dissolved in propionic acid (40mL, purity ≥ 99.5%) are heated to 120 ℃; then, 3.5mL of concentrated nitric acid (41.38mmol, 65-68% concentration) diluted with propionic acid was slowly added dropwise over 1.5h, and after about 15min, a yellow precipitate was formed; adding 20mL of propionic acid, continuously refluxing for 1h, stopping heating by TLC (thin layer chromatography) until no reactant 4-hydroxyquinoline exists, and cooling the reaction solution to room temperature; the reaction solution was filtered, the filter cake washed with petroleum ether and dried under vacuum to give a yellow solid which was 4-hydroxy-3-nitroquinoline of formula V-1 (5.28g, average yield 80.7%) with a melting 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.
The second step is that: 4-hydroxy-3-nitroquinoline (2g, 10.53mmol) of the formula V-1 was dissolved in dichloromethane, oxalyl chloride (4.5mL, 52.65mmol) was slowly added dropwise, and after the bubble generation was alleviated, the mixture was heated to 40 ℃; and concentrating the reaction solution after half an hour, wherein the obtained white solid is the 4-chloro-3-nitroquinoline of the formula VI-1, and the melting point is 116-118 ℃.
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.
The third step: 4-chloro-3-nitroquinoline of the formula VI-1 (1.37g, 6.59mmol) was dissolved in 20ml of methanol and cooled with ice water; then, 1.4ml (not less than 98%) of triethylamine and 0.6ml (not less than 99%) of ethanolamine are added, the reaction solution is stirred overnight, and the next day of filtration is carried out, so that the obtained solid is 3-nitro-4-hydroxyethylamino-quinoline (1.16g, average yield in two steps: 75.7%) of the formula III-1, and the melting point is 184-186 ℃.
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.
The fourth step: compound 4 of formula III-1 (1g, 4.29mmol) was dissolved in isopropanol and heated to 100 ℃; then, an aqueous solution (7.5 g of sodium hydrosulfite and 50ml of water) of sodium hydrosulfite (sodium dithionate) is dropped into the reaction solution, and the reaction solution is stirred for 0.5h at 100 ℃; when TLC shows that no reactant exists, stopping heating, separating out upper layer liquid, and concentrating the reaction liquid; the concentrated solid was extracted with ethanol, and the ethanol solution was concentrated to give a brown oil, i.e., 3-amino-4-hydroxyethylamino-quinoline of the formula II-1 (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.
The fifth step: placing compound 5(1.634g, 8.04mmol) of formula II-1, 1.5ml (12mol/l) of hydrochloric acid, 10ml of ethanol and 10ml of water in a single-neck bottle and cooling to 0 ℃; then, sodium nitrite 833mg is added in several times, and the reaction solution is stirred overnight; the next day, the reaction solution is filtered, the reaction solution is alkalized by NaOH until the pH value is approximately equal to 12, and the obtained precipitate is the product of the 1-ethoxyl-1H- [1,2,3] triazole [4,5-c ] quinoline of the formula I-1; if no precipitate is formed, the product can be extracted with ethyl acetate and purified by column chromatography (806mg, average yield: 48.3%) with a melting point of 170-172 ℃.
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
Subject: 6-week-old C57 male mice were divided into groups A and B, wherein group A was a cream to which 1-hydroxyethyl-1H- [1,2,3] triazolo [4,5-C ] quinoline prepared in example 1 was applied, group B was a control group to which only cream adjuvant was applied, and 5 mice per group were selected as experimental subjects.
The formula of the auxiliary materials of the cream comprises: 0.8g of glycerin monostearate, 0.8g of stearic acid, 2g of white vaseline, 8g of liquid paraffin, 10g of glycerol, 16g of water, 0.4g of sodium dodecyl sulfate, 0.2g of borneol and 1.8g of dimethyl sulfoxide. Main drugs: the content of 1-hydroxyethyl-1H- [1,2,3] triazolo [4,5-c ] quinoline prepared in example 1 was 10mg/10ml of the above-mentioned substrate.
Placing all the raw materials in 80 deg.C water bath, stirring clockwise for 30min, and cooling to room temperature.
The operation process is as follows: c57 mice were anesthetized with tribromoethanol and then smeared with molten paraffin on their backs; after the paraffin is solidified, the hairs on the back are torn off to expose the skin; on the ninth day after plucking, cyclophosphamide (20. mu.g/g) was injected; the drug is smeared on the skin of the back of the mouse for 1 time/2 day from the day of administration; smearing 40 μ l pure cream matrix on the left side, and smearing 40 μ l medicated cream on the right side; mice were sacrificed on day 21, dorsal harvest, sectioning, HE staining, and mounting.
The experimental results are as follows: compare the number of hair follicles in group A and group B in the same high power or low power field. The hair follicles on the skin on the back of the mice are dyed blue, and under the same area in the figure, the blue small spots A group are more obvious than the B group, which shows that the cream containing the 1-hydroxyethyl-1H- [1,2,3] triazole [4,5-c ] quinoline prepared in the example 1 has obvious hair follicle proliferation promoting effect on the mice (see the figures 1 to 5) and has obvious improvement effect on common alopecia, radiation and chemotherapy alopecia and hair follicle injury.
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.

Claims (7)

1. The nitrogen-containing five-membered heterocyclic quinoline compound and pharmaceutically acceptable salts thereof are characterized in that the nitrogen-containing five-membered heterocyclic quinoline compound is a compound with a structure shown in the following formula I-1:
Figure FDA0002524422450000011
2. the nitrogen-containing five-membered heterocyclic quinoline compound and the pharmaceutically acceptable salt thereof according to claim 1, wherein: the pharmaceutically acceptable salts are inorganic salts and organic salts, and are selected from one or more of hydrochloride, hydrobromide, nitrate, phosphate, metaphosphate, sulfate, sulfite, perchlorate, formate, acetate, propionate, malonate, acrylate, succinate, oxalate, D or L malate, fumarate, maleate, benzoate, hydroxybutyrate, phthalate, methanesulfonate, ethanesulfonate, sulfonate, salicylate, tartrate, citrate, lactate, mandelate and succinic acid.
3. A method for producing a nitrogen-containing five-membered heterocyclic quinoline compound according to any one of claims 1 to 2, which comprises:
the first step is as follows:
Figure FDA0002524422450000012
the second step is that:
Figure FDA0002524422450000013
the third step:
Figure FDA0002524422450000014
the fourth step:
Figure FDA0002524422450000021
the fifth step:
Figure FDA0002524422450000022
4. a pharmaceutical composition comprising the nitrogen-containing five-membered heterocycloquinoline compound of any one of claims 1 to 2 and a pharmaceutically acceptable salt thereof.
5. The pharmaceutical composition of claim 4, further comprising one or more pharmaceutically acceptable excipients.
6. Use of the nitrogen-containing five-membered heterocyclic quinoline compound and the pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or the pharmaceutical composition according to any one of claims 4 for the preparation of a medicament having a hair follicle proliferating effect.
7. Use of the nitrogen-containing five-membered heterocyclic quinoline compound and the pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or the pharmaceutical composition according to any one of claims 4 for preparing a medicament for treating alopecia universalis, alopecia due to radiotherapy and chemotherapy, and hair follicle injury.
CN201711279295.0A 2017-11-24 2017-12-06 Nitrogen-containing five-membered heterocyclic quinoline compound and salt, preparation method, pharmaceutical composition and application thereof Active CN108003153B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201711190023 2017-11-24
CN2017111900233 2017-11-24

Publications (2)

Publication Number Publication Date
CN108003153A CN108003153A (en) 2018-05-08
CN108003153B true CN108003153B (en) 2021-04-30

Family

ID=62057105

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201711279295.0A Active CN108003153B (en) 2017-11-24 2017-12-06 Nitrogen-containing five-membered heterocyclic quinoline compound and salt, preparation method, pharmaceutical composition and application thereof

Country Status (1)

Country Link
CN (1) CN108003153B (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021150613A1 (en) 2020-01-20 2021-07-29 Incyte Corporation Spiro compounds as inhibitors of kras
US11739102B2 (en) 2020-05-13 2023-08-29 Incyte Corporation Fused pyrimidine compounds as KRAS inhibitors
WO2022072783A1 (en) 2020-10-02 2022-04-07 Incyte Corporation Bicyclic dione compounds as inhibitors of kras
WO2023064857A1 (en) 2021-10-14 2023-04-20 Incyte Corporation Quinoline compounds as inhibitors of kras

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150080381A1 (en) * 2012-04-12 2015-03-19 Ironwood Pharmaceuticals, Inc. Methods of treating alopecia and acne

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
23589-53-9;REGESTRY;《STN on Web》;19841116;第1-2页 *
天然药物对毛发生长影响因素调节作用的研究进展;李云飞 等;《中草药》;20140630;第45卷(第11期);第1655-1662页 *
白木香叶挥发油化学成分的GC-MS分析;张伟等;《安徽农业科学》;20111231;第39卷(第26期);第15949页 *

Also Published As

Publication number Publication date
CN108003153A (en) 2018-05-08

Similar Documents

Publication Publication Date Title
CN108003153B (en) Nitrogen-containing five-membered heterocyclic quinoline compound and salt, preparation method, pharmaceutical composition and application thereof
ES2857085T3 (en) Valbenazine ditosylate and polymorphs thereof
CN105153122B (en) [(indol-3-yl) pyrimidine -2-base] aminophenyl propyl- 2- alkenylamide derivatives and salt, preparation method, application
AU2019218186B2 (en) Urea-substituted aromatic ring-linked dioxinoquinoline compounds, preparation method and uses thereof
JP4685243B2 (en) Pyrimido [6,1-a] isoquinolin-4-one derivatives
RU2467009C2 (en) Selective antagonists of adenosine a2a receptors
EP3686199A1 (en) Fused ring derivative as a2a receptor inhibitor
AU2011261499A1 (en) Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating proliferative diseases
CA2854836C (en) Tricyclic amino containing compounds for treatment or prevention of symptoms associated with endocrine dysfunction
WO2018217757A1 (en) Compositions and methods for preparing and using mitochondrial uncouplers
PT1559715E (en) N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-n`-(5-methyl-3-isoxazolyl)urea salt in crystalline form
CN111150731A (en) Composition containing oxirangol optical isomer or salt thereof and application
CN111166745A (en) Composition containing racemic oxypyramine or salt thereof and application
KR20240027583A (en) Pyrimidinylaminobenzene for lung cancer treatment
WO2016011195A1 (en) Th-302 solid forms and methods related thereto
JPH09208496A (en) Composition containing lh-rh antagonist
KR102436669B1 (en) Urea-substituted aromatic ring-linked dioxinoquinoline compound, preparation method and use thereof
AU2021250904A1 (en) Pyridinethiones, pharmaceutical compositions thereof, and their therapeutic use for treating a proliferative, inflammatory, neurodegenerative, or immune-mediated disease
JPS60184086A (en) Compound
JP7322140B6 (en) Novel heterocycle derivatives
CA3090876C (en) Dioxinoquinoline compounds, preparation method and uses thereof
JP7165501B2 (en) Pharmaceuticals comprising novel benzimidazole compounds
CN105829304A (en) N, n substituted piperidinamine compounds, and preparation method and usage thereof
JP5641054B2 (en) Novel compound, kinesin spindle protein inhibitor and application thereof
WO2022242582A1 (en) Indene compounds, pharmaceutical compositions thereof, and their therapeutic applications

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant