CN101948464B - 3,4,6-triaryl-(1,3)-oxazine-2-ketone compound as well as preparation method and application thereof - Google Patents
3,4,6-triaryl-(1,3)-oxazine-2-ketone compound as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN101948464B CN101948464B CN2010102698522A CN201010269852A CN101948464B CN 101948464 B CN101948464 B CN 101948464B CN 2010102698522 A CN2010102698522 A CN 2010102698522A CN 201010269852 A CN201010269852 A CN 201010269852A CN 101948464 B CN101948464 B CN 101948464B
- Authority
- CN
- China
- Prior art keywords
- oxazines
- ketone
- phenyl
- triaryl
- nitrophenyl
- 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.)
- Expired - Fee Related
Links
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemistry and relates to a 3,4,6-triaryl-(1,3)-oxazine-2-ketone compound, a preparation method thereof and also a drug composition containing the compound in a formula (I). The 3,4,6-triaryl-(1,3)-oxazine-2-ketone compound and the drug composition are used as an androgen receptor antagonist and can be used for preparing a non-steroidal drug for preventing and/or treating prostatic hyperplasia, prostate cancers, hirsutism, severe androgen-dependent alopecia or acne symptoms or diseases, associated with androgen receptors.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field; Relate to 3; 4; 6-triaryl-[1,3]-oxazines-2-ketone compounds (I) and preparation method thereof, pharmaceutical composition and in the preparation prevention or/and the purposes in the non-steroidal drug of treatment hyperplasia of prostate, prostate cancer, hirsutism, the dependent form alopecia of severe male sex hormone or acne symptom or the disease relevant with androgen receptor.
R in the formula
1, R
2, R
3, R
4Expression H, halogen, C
1～C
12Alkyl, C
1～C
12Alkoxyl group, nitro, cyanic acid, carboxyl, hydroxyl, CF
3, NR
6R
7R
6, R
7Expression H, C
1～C
12Alkyl, C
6～C
12Aryl; R
1, R
2, R
3, R
4Can be at any possible position of phenyl ring, R
1, R
2, R
3, R
4Can be identical, also can be different; Ar representes aryl, substituted aryl.
Background technology
Male sex hormone (Androgen) is the general name of hormones such as testosterone, dihydrotestosterone, adrenosterone; Mainly secrete by the mesenchymal cell of testis; Adrenal cortex and ovary also can be secreted a spot of male sex hormone, therefore in the masculinity and femininity body, all have a certain proportion of male sex hormone.Male sex hormone through with androgen receptor (Androgen Receptor; AR) combine the performance important physiological function, like the growth of the formation (prostate gland, seminal vesicle, epididymis etc.) of male fetus reproductive organ, secondal sexual character and keep, sperm generation, protein assimilation and promote cytodifferentiation and tissue growth etc.The metabolism of male sex hormone or its acceptor and dysfunction can be brought out multiple disease or quicken disease process; As: hyperplasia of prostate, prostate cancer, male sterility, hirsutism, the dependent form alopecia of severe male sex hormone and acne etc.; These diseases not only have a strong impact on patient's physiology and Mental health, and have greatly reduced their quality of life.
Benign prostatic hyperplasia is one of modal disease of Urology Surgery, has become " the stealthy killer " that threaten men's health.Clinical statistics shows, during 40～79 years old, the sickness rate of benign prostate hyperplasia is about male sex's sickness rate more than 50%, 80 years old then up to 80%.Along with rhythm of life is constantly accelerated, Benign Prostatic Hypertrophy day by day increases, and the patient has the rejuvenation of being development trend.Benign prostatic hyperplasia not only has a strong impact on patient's quality of life, also brings out multiple potential complication simultaneously easily, as: AUR, urinary tract infection, gross hematuria, vesical diverticulum, calculus, uronephrosis, renal failure etc.; Research shows that the intravital dihydrotestosterone of patient is the topmost inducement of benign prostatic hyperplasia.
Prostate cancer is the higher another kind of disease of elderly men sickness rate, and is very high at the M & M of European and American areas.Though China's prostate cancer sickness rate is lower than American-European countries; But increasing sharply along with aging population in recent years; The change of traditional food structure; Add the raising to this type medical diagnosis on disease level, sickness rate is remarkable rising tendency, and clinical investigation shows this type patient's age tendency that occurs becoming younger.The extensive concern that in worldwide, has received medical circle about the Study of Etiology and the clinical treatment of hyperplasia of prostate/prostate cancer.
Because at prostate cancer early stage/mid-term stage, 80～90% are male sex hormone dependent form, therefore, its clinical treatment mainly is to reduce male sex hormone level and the function that suppresses androgen receptor in the serum.The AR antagonist is the important means of treating prostate cancer at present clinically; Its competition combines the androgen receptor of prostate gland site of pathological change; The retardance prostatic cell is to androgenic picked-up; Suppress the effect of male sex hormone, thereby suppress the growth of tumour cell, reduce gross tumor volume and delay disease process target organ.Suppress androgenic treat-ment than other; Like male castration, take luteotropin releasing hormone d-ala analog or testosterone synthetic enzyme (like 5) suppressor factor etc.; The AR antagonist can also be blocked the male sex hormone in suprarenal gland source and combining of its acceptor, remedies the deficiency of other treat-ment.In addition, the AR antagonist can also be used to treat common diseases such as hyperplasia of prostate, hirsutism, severe male sex hormone dependent form alopecia (bald), acne.
The AR antagonist kind of using clinically at present is less, can be divided into steroidal class and nonsteroidal by chemical structure, and steroidal drug has cyproterone acetate (Cyproterone Acetate); Non-steroidal drug comprises: flutamide (Flutamide), RU-23908 (Nilufamide), bicalutamide (Bicalutamide) etc.Because it is nonsteroidal androgen antagonist medicine has than highly selective AR,, therefore more extensive in clinical application to the effect that other steroid receptor can not produce hormonelike or hormone antagonist.Yet in clinical use, finding, is that steroidal or nonsteroidal AR antagonist all exist certain spinoff, comprises causing the estrogen and androgen metabolism disorder and making gynaecomastia and hepatotoxicity etc.; Spinoffs such as hyperplasia of prostate/patients with prostate cancer people takes for a long time that flutamide or bicalutamide gastrointestinal discomfort can occur, feel sick, vomiting, insomnia, weak, headache, anxiety, blurred vision and hyposexuality; Secondly; Hyperplasia of prostate/patients with prostate cancer is single to be taken and can occur behind certain androgen antagonist medicine " androgen antagonist go down syndromes " (Antiandrogen Withdrawal Syndrome; AWS); (Prostate-specific Antigen, PSA) level rising rapidly again, gross tumor volume increase can only withdrawal or other androgen antagonist medicines of migrating for the repressed PSA of script after showing as medication for some time.The genesis mechanism of " androgen antagonist go down syndromes " it be unclear that, and is commonly considered as because the androgen receptor producer sudden change of prostatic cell makes the original medicine that plays antagonistic action produce the effect that activates androgen receptor on the contrary.Also have report to show in addition, the AR regulator exists with medicine such as antithrombotics tonka bean camphor in use and interacts.Therefore, press for the nonsteroidal androgen antagonist medicine that research and development have brand-new chemical structure clinically.
Summary of the invention
The objective of the invention is to disclose one type and have 3,4, the Nonsteroic androgen acceptor regulators of 6-triaryl-[1,3]-oxazines-2-ketone chemical structure (I);
Another object of the present invention is to disclose 3,4, the preparation method of 6-triaryl-[1,3]-oxazines-2-ketone compounds (I);
Another purpose of the present invention is to disclose 3; 4; 6-triaryl-[1,3]-oxazines-2-ketone compounds (I) in preparation prevention or/and the purposes in the non-steroidal drug of symptom such as treatment hyperplasia of prostate, prostate cancer, hirsutism, the dependent form alopecia of severe male sex hormone or the acne relevant or disease with androgen receptor.
Disclosed by the invention 3,4, the chemical structure of 6-triaryl-[1,3]-oxazines-2-ketone Nonsteroic androgen acceptor function regulator compound is shown in I:
R in the formula
1, R
2, R
3, R
4Expression H, halogen, C
1～C
12Alkyl, C
1～C
12Alkoxyl group, nitro, cyanic acid, carboxyl, hydroxyl, CF
3, NR
6R
7R
6, R
7Expression H, C
1～C
12Alkyl, C
6～C
12Aryl; R
1, R
2, R
3, R
4Can be at any possible position of phenyl ring, R
1, R
2, R
3, R
4Can be identical, also can be different; Ar representes aryl, substituted aryl.
Above-mentioned term " aryl " is meant " phenyl, furyl, thienyl, pyridyl "; " substituted aryl " be meant " substituted-phenyl ", " substituted furan base, " substituted thiophene base ", " substituted pyridinyl ", replacement can be on the Ar ring possible position arbitrarily; Used term " substituted-phenyl ", " substituted furan base ", " substituted thiophene base ", " substituted pyridinyl " are meant by 1-3 group substituted " phenyl ", " furyl ", " thienyl " and " pyridyl ": F, Cl, Br, I, C that is selected from down group
1-4Alkyl, C
1-4Alkoxyl group, nitro, amino, carboxyl, hydroxyl, cyanic acid; Preferably, substituting group is: F, Cl, Br, C
1-4Alkyl, C
1-4Alkoxyl group, nitro.
Disclosed 3,4 for the present invention, 6-triaryl-[1,3]-oxazines-2-ketone compounds (I) be configured as cis (syn) or trans (anti) or cis and trans arbitrary proportion mixture; When having chiral carbon in the molecule, compound (I) is raceme or optically active body.
Provided by the invention 3,4,6-triaryl-[1,3]-oxazines-available following method of 2-ketone compounds (I) prepares: with 1; 3-diaryl-3-aryl amine-1-acetone compounds (1) is a starting raw material, in suitable solvent, through the reductive agent reduction, gets 1, the syn of 3-diaryl-3-aryl amine-1-propanol compound and anti mixture (2); This mixture with the acylating reagent condensation, gets 3 without separation in suitable solvent; 4, the syn of 6-triaryl-[1,3]-oxazines-2-ketone compounds (I) and anti mixture (3); Through recrystallization or column chromatographic isolation and purification step, obtain 3,4 respectively then; The syn isomer and the anti isomer of 6-triaryl-[1,3]-oxazines-2-ketone compounds (I), its reaction formula is following:
Wherein, the reduction reaction solvent for use is: C
1～C
6Fatty Alcohol(C12-C14 and C12-C18), ethers (like ether, isopropyl ether, MTBE, THF etc.), halohydrocarbon (as: methylene dichloride, chloroform, 1; 2-ethylene dichloride, orthodichlorobenzene etc.), aliphatic hydrocarbon (like hexane, heptane, octane etc.), aromatic hydrocarbon or substituted aroma hydrocarbon, ETHYLE ACETATE, preferred solvent is THF, methyl alcohol, glycol dimethyl ether; Used reductive agent is: B
2H
6, BH
3SMe
2, LiAlH
4, NaAlH
4, LiHAl (OMe)
3, NaH
2Al (OCH
2CH
2OCH
3)
2, metal borohydride (as: KBH
4, NaBH
4, LiBH
4, NaBH
3CN etc.), the mixture formed of metal borohydride and acid (comprising: protonic acid, Lewis acid), preferred reductive agent is NaBH
4, KBH
4, LiAlH
4, B
2H
6, NaBH
4-ZnCl
2, NaBH
4-HOAc, NaBH
4-CaCl
2, NaBH
4-BF
3Et
2O; Reductive agent and 1, the molar feed ratio of 3-diaryl-3-aryl amine-1-acetone compounds (1) is a reductive agent: acid: substrate=0.5～10.0: 0～10.0: 1.0, preferred molar feed ratio is 0.5～5.0: 0～5.0: 1.0; Temperature of reaction is-78 ℃～150 ℃, is preferably-20 ℃～80 ℃; Reaction times is 30 minutes～72 hours, is preferably 1～15 hour.
The used acylating reagent of acylation reaction is: carbonyl diurethane amides (as: phosphinylidyne diimidazole (CDI) etc.), phosgene, superpalite, two (trichloromethyl) carbonic ether, chloroformic acid C
1-8The C of aliphatic alcohol ester compounds (as: Vinyl chloroformate, the chloroformic acid tert-butyl ester, chloroformic acid benzyl ester etc.), carbonic acid
1-8Aliphatic alcohol ester compounds (as: methylcarbonate, diethyl carbonate etc.), two succinimdyl carbonates (DSC); The acylation reaction solvent for use is: C
3-8Alkanone, C
5-10Fat alkane or naphthenic hydrocarbon (as: normal hexane, normal heptane etc.), N, dinethylformamide, ethers (as: ether, isopropyl ether, MTBE, THF, glycol dimethyl ether etc.), C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, halohydrocarbon (as: methylene dichloride, chloroform, 1; 2-ethylene dichloride, orthodichlorobenzene etc.), aromatic hydrocarbon or substituted aroma hydrocarbon, acetonitrile; Reaction can be carried out in single solvent, also can in mixed solvent, carry out, and the mixed solvent volume ratio is 1: 0.1～10; Preferred solvent is THF, N, dinethylformamide, methylene dichloride, acetone, ETHYLE ACETATE, toluene; Acylating reagent and 1, the molar feed ratio of 3-diaryl-3-aryl amine-1-propanol compound (2) is 0.3～5.0: 1.0, preferred molar feed ratio is 0.4～2.0: 1.0; Temperature of reaction is-78 ℃～150 ℃, is preferably-20 ℃～80 ℃; Reaction times is 30 minutes～24 hours, is preferably 1～15 hour.
The purification procedures method therefor is: recrystallization or column chromatography for separation, wherein, recrystallization solvent can be used C
1～C
6Fatty Alcohol(C12-C14 and C12-C18), ethers (like ether, isopropyl ether, MTBE, THF etc.), sherwood oil, C
3-8Alkanone, C
5-10Fat alkane or naphthenic hydrocarbon (as: normal hexane, normal heptane etc.), C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, recrystallization can carry out in single solvent, also can in mixed solvent, carry out, and the mixed solvent volume ratio is 1: 0.1～10, and preferred recrystallization solvent is ETHYLE ACETATE, ethyl acetate/methanol mixed solvent (proportioning is 10: 1 (v/v)); The elutriant of column chromatography for separation can be used ETHYLE ACETATE/chloroform, ethyl acetate/petroleum ether mixed solution, and its proportioning is 1～99: 99～1 (v/v); Preferred elutriant is ETHYLE ACETATE/chloroform (proportioning is 1: 30～70 (v/v)), ethyl acetate/petroleum ether (proportioning is 1: 3～6 (v/v)).
Starting raw material of the present invention-1,3-diaryl-3-aryl amine-common technology in the available this area of 1-acetone compounds (1) makes, disclosed method in the following document: Yong D.et al.CN200810044548.0.
Pharmaceutical composition provided by the invention comprise the treatment significant quantity one or more 3,4,6-triaryl-[1,3]-oxazines-2-ketone compounds (I), this pharmaceutical composition can further contain one or more pharmaceutically acceptable carrier or vehicle.
Its desired proportions of pharmaceutical composition provided by the present invention is, 3,4, and 6-triaryl-[1,3]-oxazines-2-ketone compounds (I) accounts for gross weight than 50%～99.5% as activeconstituents, and rest part is for accounting for gross weight than below 50%.
Of the present invention provide 3; 4; 6-triaryl-[1; 3]-oxazines-2-ketone compounds (I) has the androgen receptor antagonistic activity, thereby can be used for preparing prevention or/and the non-steroidal drug of symptom such as treatment hyperplasia of prostate, prostate cancer, hirsutism, severe male sex hormone dependent form alopecia or the acne relevant with androgen receptor or disease.
Embodiment
Can further describe the present invention through following embodiment, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various variations and modification to the present invention.
Embodiment 1
(syn)-preparation of 3-(4-nitrophenyl)-4-(2-thienyl)-6-(4-nitrophenyl)-[1,3]-oxazines-2-ketone (Oxazin-001)
In reaction flask, add 1-(4-nitrophenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetone (10.0mmol) and THF 40ml, after stirring at room is even, puts the cryosel bath and be cooled to 0 ℃, add NaBH in batches
4(20.0mmol), 0～5 ℃ of insulated and stirred was reacted 5 hours; Reaction is finished, and removes solvent under reduced pressure, and resistates is with in 5% the aqueous hydrochloric acid and pH to 2～3, and stirring at room was used saturated NaHCO after 10 minutes
3With pH value to 8～9, the gained mixed solution is used CHCl in the aqueous solution
3Extract CHCl
3Layer is used deionized water and saturated NaCl solution washing, anhydrous Na successively
2SO
4Drying removes solvent under reduced pressure, gets syn and anti-1-(4-nitrophenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-propanol mixture.In mixture, add anhydrous tetrahydro furan 60ml and pyridine (30.0mmol), after stirring, put the cryosel bath and be cooled to-10～-5 ℃, add two (trichloromethyl) carbonic ethers (10.0mmol), 0～5 ℃ of insulated and stirred was reacted 12 hours; Reaction is finished, and removes solvent under reduced pressure, and resistates is used CHCl
3Extract CHCl
3Layer is used deionized water and saturated NaCl solution washing, anhydrous Na successively
2SO
4Drying removes solvent under reduced pressure, and resistates is used column chromatography purification, elutriant be chloroform/ETHYLE ACETATE (50/1, v/v), collect R
fThe component of ≈ 0.25, the yellow powder solid, mp:208～210 ℃, yield 45.8%;
1H-NMR (DMSO-d
6, 400MHz) δ: 8.30 (d, J=8.8Hz, 2H, 2 * ArNO
2-H), 8.22 (d, J=8.8Hz, 2H, 2 * ArNO
2-H), 7.73 (d, J=8.8Hz, 2H, 2 * ArNO
2-H), 7.71 (d, J=8.8Hz, 2H, 2 * ArNO
2-H), 7.50 (dd, J
1=0.8Hz, J
2=4.8Hz, 1H, Ar
Thiophene-H), 7.22 (d, J=3.6Hz, 1H, Ar
Thiophene-H), 7.00 (dd, J
1=3.6Hz, J
2=4.8Hz, 1H, Ar
Thiophene-H), 5.86 (dd, J
1=2.0Hz, J
2=5.6Hz, 1H, CHO), 5.75 (dd, J
1=2.0Hz, J
2=11.2Hz, 1H, CHN), 2.86 (qd, J
1=5.6Hz, J
2=11.2Hz, J
3=14.0Hz, 1H, CH
2), 2.54 (dt, J
1=2.0Hz, J
2=14.0Hz, 1H, CH
2); ESI-MS (m/z ,+Q): 426.0 [M+H]
+
Embodiment 2
(anti)-preparation of 3-(4-nitrophenyl)-4-(2-thienyl)-6-(4-nitrophenyl)-[1,3]-oxazines-2-ketone (Oxazin-002)
Operating process is collected R with embodiment 1
fThe component of ≈ 0.15, the yellow powder solid, mp＞230 ℃, yield 10.5%;
1H-NMR (DMSO-d
6, 400MHz) δ: 8.32 (d, J=8.8Hz, 2H, 2 * Ar NO
2-H), 8.14 (d, J=8.8Hz, 2H, 2 * ArNO
2-H), 7.83 (d, J=8.8Hz, 2H, 2 * ArNO
2-H), 7.59 (d, J=8.8Hz, 2H, 2 * ArNO
2-H), 7.37 (d, J=5.2Hz, 1H, Ar
Thiophene-H), 7.00 (d, J=3.6Hz, 1H, Ar
Thiophene-H), 6.80 (dd, J
1=3.6Hz, J
2=5.2Hz, 1H, Ar
Thiophene-H), 6.00 (d, J=10.0Hz, 1H, CHO), 5.85 (dd, J
1=4.8Hz, J
2=11.2Hz, 1H, CHN), 2.88 (qd, J
1=2.0Hz, J
2=4.8Hz, J
3=14.0Hz, 1H, CH
2), 2.54～2.45 (m, 1H, CH
2); ESI-MS (m/z ,+Q): 426.1 [M+H]
+
Embodiment 3
(syn)-preparation of 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-nitrophenyl)-[1,3]-oxazines-2-ketone (Oxazin-003)
Operating process is with embodiment 1; Just 1-(4-nitrophenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetone is substituted with 1-(4-nitrophenyl)-3-(2-thienyl)-3-(4-chloroanilino)-1-acetone; The reduction reaction solvent for use substitutes with methyl alcohol; The used acylating reagent of acylation reaction substitutes with two succinimdyl carbonates, collects R
fThe component of ≈ 0.20, the pale yellow powder solid, mp:202～204 ℃, yield 42.5%;
1H-NMR (CDCl
3, 400MHz) δ: 8.26 (d, J=8.8Hz, 2H, 2 * ArNO
2-H), 7.59 (d, J=8.8Hz, 2H, 2 * ArNO
2-H), 7.33 (d, J=3.2Hz, 1H, Ar
Thiophene-H), 7.31 (d, J=8.8Hz, 2H, 2 * ArCl-H), 7.23 (d, J=8.8Hz, 2H, 2 * ArCl-H), 7.00 (d, J=3.2Hz, 2H, Ar
Thiophene-H), 5.66 (dd, J
1=2.8Hz, J
2=11.6Hz, 1H, CHN), 5.35 (dd, J
1=2.4Hz, J
2=5.2Hz, 1H, CHO), 2.65 (qd, J
1=5.2Hz, J
2=11.6Hz, J
3=14.0Hz, 1H, CH
2), 2.50 (dt, J
1=2.8Hz, J
2=14.0Hz, 1H, CH
2); ESI-MS (m/z ,+Q): 437.1 [M+Na]
+
Embodiment 4
(anti)-preparation of 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-nitrophenyl)-[1,3]-oxazines-2-ketone (Oxazin-004)
Operating process is collected R with embodiment 3
fThe component of ≈ 0.12, the pale yellow powder solid, mp＞230 ℃, yield 9.6%;
1H-NMR (CDCl
3, 400MHz) δ: 8.28 (d, J=8.8Hz, 2H, 2 * ArNO
2-H), 7.68 (d, J=8.8Hz, 2H, 2 * ArNO
2-H), 7.23 (d, J=8.8Hz, 2H, 2 * ArCl-H), 7.21 (d, J=5.2Hz, 1H, Ar
Thiophene-H), 7.09 (d, J=8.8Hz, 2H, 2 * ArCl-H), 6.77 (dd, J
1=3.6Hz, J
2=5.2Hz, 1H, Ar
Thiophene-H), 6.72 (dd, J
1=1.2Hz, J
2=3.6Hz, 1H, Ar
Thiophene-H), 5.68 (dd, J
1=2.0Hz, J
2=11.6Hz, 1H, CHN), 5.42 (dd, J
1=5.2Hz, J
2=11.6Hz, 1H, CHO), 2.78 (qd, J
1=2.0Hz, J
2=11.6Hz, J
3=14.4Hz, 1H, CH
2), 2.57 (qd, J
1=5.2Hz, J
2=11.5Hz, J
3=14.4Hz, 1H, CH
2); ESI-MS (m/z ,+Q): 437.1 [M+Na]
+
Embodiment 5
(syn)-preparation of 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-fluorophenyl)-[1,3]-oxazines-2-ketone (Oxazin-005)
Operating process just substitutes 1-(4-nitrophenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetone NaBH with embodiment 1 with 1-(4-fluorophenyl)-3-(2-thienyl)-3-(4-chloroanilino)-1-acetone
4Use B
2H
6Substitute, the used acylating reagent of acylation reaction substitutes with CDI, and the acylation reaction solvent for use is used CH
2Cl
2Substitute, the gained mixture use re-crystallizing in ethyl acetate, must the white powder solid, and mp:196～198 ℃, yield 46.5%;
1H-NMR (CDCl
3, 400MHz) δ: 7.40～7.36 (m, 2H, 2 * ArF-H), 7.31～7.28 (m, 3H, 2 * ArCl-H+Ar
Thiophene-H), 7.22 (d, J=8.8Hz, 2H, 2 * ArCl-H), 7.10～7.06 (m, 2H, 2 * ArF-H), 6.99～6.97 (m, 2H, Ar
Thiophene-H), 5.64 (dd, J
1=2.8Hz, J
2=11.6Hz, 1H, CHN), 5.32 (dd, J
1=2.4Hz, J
2=5.6Hz, 1H, CHO), 2.67 (qd, J
1=5.6Hz, J
2=11.6Hz, J
3=15.6Hz, 1H, CH
2), 2.50 (dt, J
1=2.8Hz, J
2=15.6Hz, 1H, CH
2); ESI-MS (m/z ,+Q): 410.2 [M+Na]
+
Embodiment 6
(syn)-preparation of 3-(4-nitrophenyl)-4-(2-thienyl)-6-(4-aminomethyl phenyl)-[1,3]-oxazines-2-ketone (Oxazin-006)
Operating process just substitutes 1-(4-nitrophenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetone with embodiment 1 with 1-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetone, collect R
fThe component of ≈ 0.28, the yellow powder solid, mp:199～201 ℃, yield 51.3%;
1H-NMR (CDCl
3, 400MHz) δ: 8.10 (d, J=9.2Hz, 2H, 2 * ArNO
2-H), 7.40 (d, J=9.2Hz, 2H, 2 * ArNO
2-H), 7.35 (d, J=8.0Hz, 2H, 2 * ArCH
3-H), 7.25 (d, J=8.0Hz, 2H, 2 * ArCH
3-H), 7.16 (d, J=4.0Hz, 1H, Ar
Thiophene-H), 6.77 (m, 2H, 2 * Ar
Thiophene-H), 5.56～5.51 (m, 2H, CHN+CHO), 2.73 (qd, J
1=2.0Hz, J
2=5.6Hz, J
3=14.4Hz, 1H, CH
2), 2.67 (dt, J
1=2.8Hz, J
2=14.4Hz, 1H, CH
2); ESI-MS (m/z ,+Q): 417.3 [M+Na]
+
Embodiment 7
(anti)-preparation of 3-(4-nitrophenyl)-4-(2-thienyl)-6-(4-aminomethyl phenyl)-[1,3]-oxazines-2-ketone (Oxazin-007)
Operating process is collected R with embodiment 6
fThe component of ≈ 0.15, the yellow powder solid, mp＞230 ℃, yield 11.7%;
1H-NMR (CDCl
3, 400MHz) δ: 8.16 (d, J=9.2Hz, 2H, 2 * ArNO
2-H), 7.50 (d, J=9.2Hz, 2H, 2 * ArNO
2-H), 7.31 (d, J=4.0Hz, 1H, Ar
Thiophene-H), 7.27 (d, J=8.0Hz, 2H, 2 * ArCH
3-H), 7.20 (d, J=8.0Hz, 2H, 2 * ArCH
3-H), 6.98 (d, J=4.0Hz, 2H, Ar
Thiophene-H), 5.60 (dd, J
1=2.4Hz, J
2=11.2Hz, 1H, CHN), 5.43 (dd, J
1=3.2Hz, J
2=5.6Hz, 1H, CHO), 2.75～2.67 (m 1H, CH
2), 2.54～2.52 (m, 1H, CH
2); ESI-MS (m/z ,+Q): 417.2 [M+Na]
+
Embodiment 8
(syn)-preparation of 3-(4-nitrophenyl)-4-(2-thienyl)-6-(4-chloro-phenyl-)-[1,3]-oxazines-2-ketone (Oxazin-008)
Operating process is with embodiment 1; Just 1-(4-nitrophenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetone is substituted with 1-(4-chloro-phenyl-)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetone; The yellow powder solid, mp:153～155 ℃, yield 46.2%;
1H-NMR (CDCl
3, 600MHz) δ: 8.19 (d, J=9.0Hz, 2H, 2 * ArNO
2-H), 7.51 (d, J=9.0Hz, 2H, 2 * ArNO
2-H), 7.41 (d, J=3.0Hz, 1H, Ar
Thiophene-H), 7.39 (d, J=8.4Hz, 2H, 2 * ArCl-H), 7.33 (d, J=8.4Hz, 2H, 2 * ArCl-H), 6.99 (d, J=3.0Hz, 2H, Ar
Thiophene-H), 5.57 (d, J=10.8Hz, 1H, CHN), 5.45 (dd, J
1=3.0Hz, J
2=5.4Hz, 1H, CHO), 2.76～2.69 (m 1H, CH
2), 2.53～2.49 (m, 1H, CH
2); ESI-MS (m/z ,+Q): 437.4 [M+Na]
+
Embodiment 9
(anti)-preparation of 3-(4-nitrophenyl)-4-(2-thienyl)-6-(4-chloro-phenyl-)-[1,3]-oxazines-2-ketone (Oxazin-009)
Operating process is collected R with embodiment 8
fThe component of ≈ 0.15, the yellow powder solid, mp＞230 ℃, yield 9.0%;
1H-NMR (CDCl
3, 400MHz) δ: 8.12 (d, J=9.0Hz, 2H, 2 * ArNO
2-H), 7.40 (d, J=9.0Hz, 2H, 2 * ArNO
2-H), 7.39 (d, J=8.4Hz, 2H, 2 * ArCl-H), 7.32 (d, J=8.4Hz, 2H, 2 * ArCl-H), 7.18 (dd, J
1=1.2Hz, J
2=4.2Hz, 1H, Ar
Thiophene-H), 6.77～6.75 (m, 2H, Ar
Thiophene-H), 5.55 (d, J=5.4Hz, 1H, CHN), 5.53 (dd, J
1=3.0Hz, J
2=5.4Hz, 1H, CHO), 2.68～2.67 (m, 1H, CH
2); ESI-MS (m/z ,+Q): 437.2 [M+Na]
+
Embodiment 10～16
Operating process is with embodiment 1, just with 1-(4-nitrophenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetone with corresponding 1,3-diaryl-3-aryl amine-1-acetone compounds is alternative, can prepare following compound:
Embodiment 17 biological activity tests
1. material installation
1.1 plasmid and cell strain
Expression of androgen receptor plasmid and luciferase reporter gene plasmid are made up by The National Center for Drug Screening; Human breast cancer cell strain MDA-MB-453 and monkey renal epithelial cell CV-1 are all available from U.S. ATCC.
1.2 reagent
Foetal calf serum (Fetal bovine serum, FBS, GIBCO/BRL, USA); Gac and VISOSE processing foetal calf serum (CD-FBS, Hyclone, USA); DMEM and RPMI 1640 substratum (GIBCO/BRL, USA); The IMEM substratum (Bioresource, USA); The luciferase detection kit (Promega Corporation, USA); Fugene 6 (Roche Ltd., USA); [
3H]-dihydrotestosterone (Dehydrotestosterone, DHT, Amersham, UK); Scintillation solution (SuperMixTM, PerkinElmer, USA).
1.3 instrument
Envision 2101 Multilabel Reader (PerkinElmer, USA); CO2gas incubator (Forma, USA); Wallac MicroBeta
TriLux 1450 (PerkinElmer, USA); VERSA
MaxMicroplateReader (Molecular Devices, USA).
2. experimental technique and result
2.1 reporter gene expression detects
2.2.1 agonist activity pattern
The MDA-MB-453 cell is cultivated in the IMEM substratum that contains 10%FBS and 2mML type glutaminate (L-glutamine), and transfection changes the IMEM substratum that contains 5%CD-FBS into previous day, and Fugene 6 reagent are adopted in transfection.Reporter gene carrier and Fugene 6 are evenly dropwise added in the cell with 1: 3 mixed, at 37 ℃ and 5%CO
2Cultivated 6 hours under the condition, insert 96 well culture plates with 20000/100 μ l/ holes behind the cell dissociation, cultivate based on 37 ℃ with the IMEM that contains 5%CD-FBS and cultivated 2 hours.Add institute's synthetic of the present invention target compound to be measured; And with 5 α-dihydrotestosterone (5 α-DHT) are the agonist positive control; In CO2gas incubator, cultivate after 24 hours, detect enzymic activity, assess the agonist activity of compound androgen receptor with this with the plain detection kit of luciferase.With 1 μ M DHT institute inductive reporter gene activity is 100%, calculates the relative agonist activity of each target compound.
2.2.2 antagonistic activity pattern
The MDA-MB-453 cell is cultivated in the IMEM substratum that contains 10%FBS and 2mM L type glutaminate (L-glutamine).Transfection changes the IMEM substratum that contains 5%CD-FBS into previous day, and Fugene 6 reagent are adopted in transfection.Reporter gene carrier and Fugene 6 are evenly dropwise added in the cell with 1: 3 mixed, at 37 ℃ and 5%CO
2Cultivated 6 hours under the condition, insert 96 well culture plates with 20000/100 μ l/ holes behind the cell dissociation, cultivate based on 37 ℃ with the IMEM that contains 5%CD-FBS and cultivated 2 hours.Add institute's synthetic of the present invention target compound to be measured; Adding 5nM DHT behind the 30min is agonist; And be the antagonist positive control with bicalutamide (BCA); In CO2gas incubator, cultivate after 24 hours, use the luciferase detection kit and detect enzymic activity, assess the antagonistic activity of compound androgen receptor with this.Being suppressed DHT inductive reporter gene activity with 10 μ M bicalutamides is 90%, calculates the relative antagonistic activity of each target compound.
2.2 reporter gene expression detected result
The reporter gene expression detected result of target compound is seen table 1:
Table 13,4, the reporter gene expression detected result of 6-triaryl-[1,3]-oxazines-2-ketone compounds
" n.a. " expression " not active "
3. experiment conclusion
The selection result shows that in activation pattern, the gained compound does not all have the androgen receptor agonist activity, and in the antagonism pattern, majority of compounds has certain androgen receptor antagonistic activity, and anti is stronger slightly than the antagonistic activity of syn configuration.
Test result shows; 3; 4; 6-triaryl-[1; 3]-oxazine-2-ketone compounds has exploitation becomes the potentiality of novel androgen receptor function regulator, can be used for preparing prevention or/and treatment because symptom or the disease that male sex hormone and androgen receptor functional disorder cause, as: middle-aging male male sex hormone partly lack syndrome, osteoporosis, muscle wasting, femal sexual function not entirely, apocleisis, emaciation, mammary cancer, hyperplasia of prostate, prostate cancer, hirsutism, the alopecia of severe male sex hormone dependent form, acne, alzheimer's disease and parkinsonism etc.
Claims (10)
1. one type 3,4,6-triaryl-[1,3]-oxazines-2-ketone compounds (I) is characterized in that it is the compound with following chemical structure of general formula:
This compounds is the arbitrary proportion mixture of anti configuration or syn configuration and anti configuration, R in the formula
1, R
2, R
3, R
4Expression H, halogen, C
1～C
12Alkyl, C
1～C
12Alkoxyl group, nitro, cyanic acid, carboxyl, hydroxyl, CF
3, NR
6R
7R
6, R
7Expression H, C
1～C
12Alkyl, C
6～C
12Aryl; R
1, R
2, R
3, R
4Can be at any possible position of phenyl ring, R
1, R
2, R
3, R
4Can be identical, also can be different; Ar representes phenyl, furyl, thienyl or pyridyl, also can represent to be selected from F, Cl, Br, I, C by 1-3
1-4Alkyl, C
1-4Alkoxyl group, nitro, amino, carboxyl, hydroxyl or the substituted phenyl of cyanic acid, furyl, thienyl or pyridyl.
2. as claimed in claim 13,4,6-triaryl-[1,3]-oxazines-2-ketone compounds; It is characterized in that said compound is selected from: 3-(4-nitrophenyl)-4-(2-thienyl)-6-(4-nitrophenyl)-[1,3]-oxazines-2-ketone; 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-nitrophenyl)-[1,3]-oxazines-2-ketone, 3-(4-nitrophenyl)-4-(2-thienyl)-6-(4-chloro-phenyl-)-[1; 3]-oxazines-2-ketone, 3-(4-nitrophenyl)-4-phenyl-6-(4-chloro-phenyl-)-[1,3]-oxazines-2-ketone; 3-[(4-chloro-3-nitro) phenyl]-4-phenyl-6-(4-bromophenyl)-[1,3]-oxazines-2-ketone, 3-[(4-nitro-3-trifluoromethyl) phenyl]-4-(2-furyl)-6-(4-chloro-phenyl-)-[1; 3]-oxazines-2-ketone, 3-(4-nitrophenyl)-4-(2-furyl)-6-(4-chloro-phenyl-)-[1,3]-oxazines-2-ketone; 3-(4-nitrophenyl)-4-(3-pyridyl)-6-(4-chloro-phenyl-)-[1,3]-oxazines-2-ketone, 3-(4-cyano-phenyl)-4-(4-chloro-phenyl-)-6-(4-p-methoxy-phenyl)-[1; 3]-oxazines-2-ketone, 3-(4-carboxyl phenyl)-4-(4-nitrophenyl)-6-(4-hydroxy phenyl)-[1,3]-oxazines-2-ketone.
3. one type 4,6-triaryl-[1,3]-oxazines-2-ketone compounds (I); It is characterized in that this compounds is: (syn)-3-(4-nitrophenyl)-4-(2-thienyl)-6-(4-nitrophenyl)-[1; 3]-oxazines-2-ketone, (syn)-3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-nitrophenyl)-[1,3]-oxazines-2-ketone; (syn)-3-(4-nitrophenyl)-4-(2-thienyl)-6-(4-chloro-phenyl-)-[1,3]-oxazines-2-ketone.
4. each is described 3,4 like claim 1～3, the preparation method of 6-triaryl-[1,3]-oxazines-2-ketone compounds; It is characterized in that with 1,3-diaryl-3-aryl amine-1-acetone compounds (1) is a starting raw material, in suitable solvent, reduces through reductive agent; 1, the syn of 3-diaryl-3-aryl amine-1-propanol compound and anti mixture (2), this mixture be without separation, in suitable solvent with the acylating reagent condensation; Get 3,4, the syn of 6-triaryl-[1,3]-oxazines-2-ketone compounds (I) and anti mixture (3); Through recrystallization or column chromatographic isolation and purification step, obtain 3,4 respectively then; The syn isomer and the anti isomer of 6-triaryl-[1,3]-oxazines-2-ketone compounds (I), its reaction formula is following:
5. as claimed in claim 43,4, the preparation method of 6-triaryl-[1,3]-oxazines-2-ketone compounds is characterized in that the reduction reaction solvent for use is: C
1～C
6Fatty Alcohol(C12-C14 and C12-C18), ethers, halohydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, substituted aroma hydrocarbon or ETHYLE ACETATE; Used reductive agent is: B
2H
6, BH
3SMe
2, LiAlH
4, NaAlH
4, LiHAl (OMe)
3, NaH
2Al (OCH
2CH
2OCH
3)
2, the mixture formed of metal borohydride or metal borohydride and acid; Temperature of reaction is-78 ℃～150 ℃; Reaction times is 30 minutes～72 hours.
6. as claimed in claim 43; 4, the preparation method of 6-triaryl-[1,3]-oxazines-2-ketone compounds; It is characterized in that the used acylating reagent of acylation reaction is: carbonyl diurethane amides, phosgene, superpalite, two (trichloromethyl) carbonic ether, chloroformic acid C
1-8The C of aliphatic alcohol ester, carbonic acid
1-8Aliphatic alcohol ester or two succinimdyl carbonates; The acylation reaction solvent for use is: C
3-8Alkanone, C
5-10Fat alkane or naphthenic hydrocarbon, N, dinethylformamide, ethers, C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, halohydrocarbon, aromatic hydrocarbon, substituted aroma hydrocarbon or acetonitrile; Acylating reagent and 1, the molar feed ratio of 3-diaryl-3-aryl amine-1-propanol compound (2) is 0.3～5.0: 1.0; Temperature of reaction is-78 ℃～150 ℃; Reaction times is 30 minutes～24 hours.
7. as claimed in claim 43,4, the preparation method of 6-triaryl-[1,3]-oxazines-2-ketone compounds, it is characterized in that the purification procedures method therefor is: recrystallization or column chromatography for separation, recrystallization solvent is selected from C
1～C
6Fatty Alcohol(C12-C14 and C12-C18), ethers, sherwood oil, C
3-8Alkanone, C
5-10Fat alkane or naphthenic hydrocarbon or C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms; The elutriant of column chromatography for separation is selected from ETHYLE ACETATE/chloroform, ethyl acetate/petroleum ether mixed solution, and its proportioning is a volume ratio 1～99/99～1.
8. pharmaceutical composition; Each is described 3,4 like claim 1～3 for one or more that comprise the treatment significant quantity, 6-triaryl-[1; 3]-oxazines-2-ketone compounds, this pharmaceutical composition further contains one or more pharmaceutically acceptable carrier or vehicle.
9. pharmaceutical composition as claimed in claim 8 is characterized in that described compound accounts for gross weight than 50%～99.5% as activeconstituents.
As claim 1～3 each described 3; 4; 6-triaryl-[1,3]-oxazines-2-ketone compounds as the Nonsteroic androgen acceptor antagonist in preparation prevention or/and the purposes in the non-steroidal drug of treatment hyperplasia of prostate, prostate cancer, hirsutism, the dependent form alopecia of severe male sex hormone or acne symptom or the disease relevant with androgen receptor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102698522A CN101948464B (en) | 2010-09-02 | 2010-09-02 | 3,4,6-triaryl-(1,3)-oxazine-2-ketone compound as well as preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102698522A CN101948464B (en) | 2010-09-02 | 2010-09-02 | 3,4,6-triaryl-(1,3)-oxazine-2-ketone compound as well as preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101948464A CN101948464A (en) | 2011-01-19 |
| CN101948464B true CN101948464B (en) | 2012-02-15 |
Family
ID=43452106
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102698522A Expired - Fee Related CN101948464B (en) | 2010-09-02 | 2010-09-02 | 3,4,6-triaryl-(1,3)-oxazine-2-ketone compound as well as preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101948464B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101250136A (en) * | 2008-04-08 | 2008-08-27 | 四川大学 | 1,3-diaryl-3-aryl amidine-1-acetoxime compounds, preparation method and use thereof |
| CN101250134A (en) * | 2008-04-08 | 2008-08-27 | 四川大学 | N-aryl-beta-aryl amidine-propionamide compounds, preparation method and use thereof |
| CN101805326A (en) * | 2010-04-06 | 2010-08-18 | 四川大学 | 1,3-diaryl-3-aromatic amino-1-propanol compound and preparation method and application thereof |
-
2010
- 2010-09-02 CN CN2010102698522A patent/CN101948464B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101250136A (en) * | 2008-04-08 | 2008-08-27 | 四川大学 | 1,3-diaryl-3-aryl amidine-1-acetoxime compounds, preparation method and use thereof |
| CN101250134A (en) * | 2008-04-08 | 2008-08-27 | 四川大学 | N-aryl-beta-aryl amidine-propionamide compounds, preparation method and use thereof |
| CN101805326A (en) * | 2010-04-06 | 2010-08-18 | 四川大学 | 1,3-diaryl-3-aromatic amino-1-propanol compound and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101948464A (en) | 2011-01-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20230129598A1 (en) | Methods of treating estrogen receptor-associated diseases | |
| AU2014262333B2 (en) | Ester derivatives of androgen receptor modulators and methods for their use | |
| US6469007B2 (en) | Serotonergic agents | |
| CN107848974A (en) | Aromatic sulfonamides derivative | |
| CN101711756B (en) | Application of 3-phenyl-3-(4-nitryl phenylamino)-1-(4-chlorphenyl)-1-acetone as non-steroidal androgen receptor regulating agent | |
| JP2016530285A (en) | Halogenated compounds for imaging and treatment of cancer and methods of use thereof | |
| BRPI0610956A2 (en) | benzofuran derivatives with therapeutic activities | |
| KR20130016041A (en) | Novel aniline derivatives and use thereof | |
| CN104955809B (en) | The purposes of substituted acetylene-derivative and its positive allosteric modulators as mGluR4 | |
| KR102119372B1 (en) | Indole carboxamide derivative | |
| CN101948464B (en) | 3,4,6-triaryl-(1,3)-oxazine-2-ketone compound as well as preparation method and application thereof | |
| CN101921266B (en) | 3,4,6-triaryl-[1,3]-oxazine compound as well as preparation method and application thereof | |
| CN101805326A (en) | 1,3-diaryl-3-aromatic amino-1-propanol compound and preparation method and application thereof | |
| JP5841128B2 (en) | Regulators of fatty acid amide hydrolase | |
| CN101250134B (en) | N-aryl-beta-aryl amidine-propionamide compounds, preparation method and use thereof | |
| AU2017389819A1 (en) | Azabicyclo-substituted triazole derivative, preparation method thereof, and application of same in medicine | |
| CN101648933B (en) | 3,4-dihydro-4-oxygen-2H-1-chromene mannich base compound as well as preparation method and application thereof | |
| CN101250136A (en) | 1,3-diaryl-3-aryl amidine-1-acetoxime compounds, preparation method and use thereof | |
| KR20010023742A (en) | Piperidinylmethyloxazolidinone derivative | |
| US7816362B2 (en) | Serotonergic agents | |
| KR20130088905A (en) | Substituted pyridine derivatives | |
| JP2012184224A (en) | COMPOUND OR PHARMACOLOGICALLY ACCEPTABLE SALT THEREOF, HAVING ACTIVITY FOR INHIBITING AGGREGATION OF AMYLOID β-PROTEIN, METHOD FOR PRODUCING THE SAME, AND APPLICATION THEREOF | |
| CZ2000948A3 (en) | Substituted chroman derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120215 Termination date: 20140902 |
|
| EXPY | Termination of patent right or utility model |