CN101921266A - 3,4,6-triaryl-[1,3]-oxazine compound as well as preparation method and application thereof - Google Patents
3,4,6-triaryl-[1,3]-oxazine compound as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of medicinal chemistry, relating to a 3,4,6-triaryl-[1,3]-oxazine compound (I) and a preparation method thereof, as well as a medicament composition containing the compound shown as the formula (I). The compound and the medicament composition can be used as an androgen receptor antagonist for preparing non-steroidal medicaments for preventing or/and treating symptoms or diseases relevant to androgen receptors, such as benign prostatic hyperplasia, prostate cancer, female hirsutism and severe androgen-dependent alopecia or acnes.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to 3,4,6-triaryl-[1,3]-oxazine 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, cyano group, carboxyl, hydroxyl, CF
3R
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 represents aryl, substituted aryl; R
5Expression H, C
1～C
12Alkyl, C
3～C
7Cycloalkyl, C
6～C
12Aryl, furyl, thienyl, pyridyl, carboxyl.
Background technology
Male sex hormone (Androgen) is the general name of hormones such as testosterone, dihydrotestosterone, adrenosterone, and mainly by the interstitial glands secretion, adrenal cortex and ovary also can be secreted a small amount of male sex hormone, therefore all has the certain proportion male sex hormone in the masculinity and femininity body.Male sex hormone by with androgen receptor (Androgen Receptor, AR) in conjunction with the performance important physiological function, as the male fetus reproductive organ form the growth of (prostate gland, seminal vesicle, epididymis etc.), 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 have not only had 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 has not only had a strong impact on patient's quality of life, also brings out multiple potential complication easily simultaneously: as acute urinary retention, urinary tract infection, gross hematuria, vesical diverticulum, calculus, uronephrosis, renal failure etc.Studies show 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 raising to this class medical diagnosis on disease level, sickness rate is remarkable rising tendency, and clinical investigation shows this class patient's age tendency that occurs becoming younger.The extensive concern that in worldwide, has been subjected to 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 for the treatment of prostate cancer at present clinically, its competition is in conjunction with 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 to target organ, thereby suppress the growth of tumour cell, reduce gross tumor volume and delay disease process.Suppress androgenic methods of treatment than other, as male castration, take luteotropin releasing hormone d-ala analog or testosterone synthetic enzyme (as 5) inhibitor 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 methods of treatment.In addition, the AR antagonist can also be used for the treatment of common diseases such as hyperplasia of prostate, hirsutism, severe male sex hormone dependent form alopecia (bald), acne.
The AR antagonist kind of using clinically is less at present, 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), 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 finding in clinical use, is that steroidal or nonsteroidal AR antagonist all exist certain side effect, comprises causing the estrogen and androgen metabolism disorder and making gynaecomastia and hepatotoxicity etc.; Side effects 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), show as after medication for some time repressed prostate specific antigen (Prostate-specific Antigen originally, PSA) level rising rapidly again, gross tumor volume increase can only withdrawal or other androgen antagonist medicines of migrating.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 conditioning agent 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 object of the present invention is to provide a class to have 3,4, the Nonsteroic androgen acceptor regulators of 6-triaryl-[1,3]-oxazine class chemical structures (I);
Another object of the present invention is to provide 3,4, the preparation method of 6-triaryl-[1,3]-oxazine compounds (I);
Another purpose of the present invention is to provide 3,4,6-triaryl-[1,3]-oxazine 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.
Provided by the invention 3,4, the chemical structure of 6-triaryl-[1,3]-oxazine non-steroid androgen receptor function regulator compounds 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, cyano group, carboxyl, hydroxyl, CF
3R
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 represents aryl, substituted aryl; R
5Expression H, C
1～C
12Alkyl, C
3～C
7Cycloalkyl, C
6～C
12Aryl, furyl, thienyl, pyridyl, carboxyl.
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 " phenyl " that group replaced, " 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, cyano group; Preferably, substituting group is: F, Cl, Br, C
1-4Alkyl, C
1-4Alkoxyl group, nitro.
For disclosed in this invention 3,4,6-triaryl-[1,3]-oxazine 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] the available following method of-oxazine compounds (I) prepares: with 1,3-diaryl-3-aryl amine-1-acetone compounds (1) is a starting raw material, reduces through reductive agent in suitable solvent, get 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 aldehyde compound R
5CHO or its hemiacetal or acetal cyclization, get 3,4, the syn of 6-triaryl-[1,3]-oxazine compounds (I) and anti mixture (3), then through recrystallization or column chromatographic isolation and purification step, obtain 3,4 respectively, 6-triaryl-[1,3] the syn isomer of-oxazine compounds (I) and anti isomer, its chemical equation is as follows:
Wherein, the reduction reaction solvent for use is: C
1～C
6Fatty Alcohol(C12-C14 and C12-C18), ethers (as ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF) etc.), halohydrocarbon (as: methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene etc.), aliphatic hydrocarbon (as hexane, heptane, octane etc.), aromatic hydrocarbon or substituted aroma hydrocarbon, ethyl acetate, preferred solvent is tetrahydrofuran (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 ring-closure reaction solvent for use is: water, C
3-8Aliphatic ketone, C
5-10Fat alkane or naphthenic hydrocarbon (as: normal hexane, normal heptane etc.), N, dinethylformamide, ethers (as: ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (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, pyridine, reaction can be carried out in single solvent, also can in the mixture of above-mentioned two kinds of solvents, carry out, the mixed solvent volume ratio is 1: 0.1～10, and preferred solvent is tetrahydrofuran (THF), ethanol, acetone, ethyl acetate, methylene dichloride; Aldehyde compound can be used R
5CHO or itself and C
1-6The formed hemiacetal of Fatty Alcohol(C12-C14 and C12-C18) or itself and C
1-6Formed acetal of Fatty Alcohol(C12-C14 and C12-C18) or R
5CHO self-polymerization thing (as: trioxymethylene, paraldehyde, Paraformaldehyde 96 etc.), the preferred aldehydes compounds is free R
5CHO; Aldehyde compound 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 0.4～2.5: 1.0; Temperature of reaction is-20 ℃～150 ℃, is preferably 0 ℃～50 ℃; Reaction times is 1 hour～48 hours, is preferably 3～24 hours.
The purification procedures method therefor is: recrystallization or column chromatography, wherein, recrystallization solvent can be used C
1～C
6Fatty Alcohol(C12-C14 and C12-C18), ethers (as ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF) etc.), sherwood oil, C
3-8Aliphatic ketone, 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 carry out in mixed solvent, and the mixed solvent volume ratio is 1: 0.1～10, and preferred recrystallization solvent is ethyl acetate, ethyl acetate/methanol mixed solvent (proportioning is 10: 1 (v/v)); The elutriant of column chromatography for separation can be used sherwood oil/chloroform, petrol ether/ethyl acetate mixed solution, and its proportioning is 1～99/99～1 (v/v); Preferred elutriant is sherwood oil/chloroform (proportioning is 3～6/1 (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.
Pharmaceutical composition provided by the invention comprise the treatment significant quantity one or more 3,4,6-triaryl-[1,3]-oxazine compounds (I), said composition can further contain one or more pharmaceutically acceptable carrier or vehicle.
Its ideal ratio of pharmaceutical composition provided by the present invention is, 3,4, and 6-triaryl-[1,3]-oxazine compounds (I) account 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]-oxazine compounds (I) have 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 by the following examples, 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)-3, the preparation of 6-two (4-aminomethyl phenyl)-4-(2-thienyl)-[1,3]-oxazines (HCHO-001)
In reaction flask, add 1-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-toluidine)-1-acetone (10.0mmol) and tetrahydrofuran (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, resistates with in 5% the aqueous hydrochloric acid with pH to 2～3, stirring at room was used saturated NaHCO after 10 minutes
3In the aqueous solution and pH value to 8～9, gained mixed solution CHCl
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-aminomethyl phenyl)-3-(2-thienyl)-3-(4-toluidine)-1-propanol mixture.In mixture, add tetrahydrofuran (THF) 60ml and 37% formalin (30.0mmol), stirring at room reaction 20 hours; Reaction is finished, and removes solvent under reduced pressure, resistates CHCl
3Extract CHCl
3Layer is used deionized water and saturated NaCl solution washing, anhydrous Na successively
2SO
4Drying removes solvent under reduced pressure, resistates column chromatography purification, elutriant be sherwood oil/chloroform (3/1, v/v), collect R
fThe component of ≈ 0.25, the white powder solid, mp:76～78 ℃, yield 54.6%;
1H-NMR (CDCl
3, 400MHz) δ: 7.34～7.06 (m, 11H, Ar-H), 5.13 (dd, J
1=1.2Hz, J
2=11.6Hz 1H, CHO), 5.05 (d, J=11.2Hz, 2H, OCH
2N), 4.84 (dd, J
1=2.0Hz, J
2=11.6Hz, 1H, CHN), 2.35 (qd, J
1=11.2Hz, J
2=11.6Hz, J
3=14.0Hz, 1H, CH
2), 2.34 (s, 3H, CH
3), 2.33 (s, 3H, CH
3), 2.14 (dt, J
1=1.6Hz, J
2=14.0Hz, 1H, CH
2); ESI-MS (m/z ,+Q): 372.3[M+Na]
+
Embodiment 2
(anti)-3, the preparation of 6-two (4-aminomethyl phenyl)-4-(2-thienyl)-[1,3]-oxazines (HCHO-002)
Operating process is collected R with embodiment 1
fThe component of ≈ 0.15, the white powder solid, mp:131～133 ℃, yield 17.2%;
1H-NMR (CDCl
3, 400MHz) δ: 7.32 (d, J=8.0Hz, 2H, 2 * Ar-H), 7.17 (d, J=8.0Hz, 2H, 2 * Ar-H), 7.12 (dd, J
1=1.2Hz, J
2=4.8Hz, 1H, Ar
Thiophene-H), 7.03 (d, J=8.4Hz, 2H, 2 * Ar-H), 6.99 (d, J=8.4Hz, 2H, 2 * Ar-H), 6.85 (d, J=4.8Hz, 1H, Ar
Thiophene-H), 6.83 (dd, J
1=1.2Hz, J
2=4.8Hz, 1H, Ar
Thiophene-H), 5.11 (d, J=9.6Hz, 1H, OCH
2N), 4.78 (dd, J
1=3.6Hz, J
2=12.0Hz 1H, CHO), 4.74 (d, J=9.6Hz, 1H, OCH
2N), 4.71 (dd, J
1=2.8Hz, J
2=12.8Hz, 1H, CHN), 2.34 (s, 3H, CH
3), 2.33 (s, 3H, CH
3), 2.24 (s, 3H, CH
3), 2.29～2.17 (m, 2H, CH
2); ESI-MS (m/z ,+Q): 372.2[M+Na]
+
Embodiment 3
(syn)-preparation of 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-aminomethyl phenyl)-[1,3]-oxazines (HCHO-003)
Operating process is with embodiment 1, just 1-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-toluidine)-1-acetone is substituted with 1-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-chloroanilino)-1-acetone, the reduction reaction solvent for use substitutes with methyl alcohol, the ring-closure reaction solvent for use substitutes with ethanol, collects R
fThe component of ≈ 0.25, the white powder solid, mp:97～99 ℃, yield 60.8%;
1H-NMR (CDCl
3, 400MHz) δ: 7.35～7.06 (m, 11H, Ar-H), 5.12 (dd, J
1=2.0Hz, J
2=11.6Hz, 1H, CHO), 5.05 (d, J=12.0Hz, 2H, OCH
2N), 4.85 (dd, J
1=2.0Hz, J
2=11.6Hz, 1H, CHN), 2.34 (s, 3H, CH
3), 2.32 (m, 1H, CH
2), 2.17 (dt, J
1=2.0Hz, J
2=14.0Hz, 1H, CH
2); ESI-MS (m/z ,+Q): 393.2[M+Na]
+
Embodiment 4
(anti)-preparation of 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-aminomethyl phenyl)-[1,3]-oxazines (HCHO-004)
Operating process is collected R with embodiment 3
fThe component of ≈ 0.15, the white powder solid, mp:121～123 ℃, yield 21.0%;
1H-NMR (CDCl
3, 400MHz) δ: 7.31 (d, J=8.0Hz, 2H, 2 * Ar-H), 7.18 (d, J=8.0Hz, 2H, 2 * Ar-H), 7.16～7.13 (m, 3H, 2 * Ar-H+Ar
Thiophene-H), 7.04 (d, J=8.8Hz, 2H, 2 * Ar-H), 6.88～6.85 (m, 2H, 2 * Ar
Thiophene-H), 5.12 (d, J=10.0Hz, 1H, OCH
2N), 4.82 (d, J=10.8Hz, CHO), 4.80 (d, J=10.0Hz, 1H, OCH
2N), 4.73 (dd, J
1=3.2Hz, J
2=11.2Hz, 1H, CHN), 2.35 (s, 3H, CH
3), 2.32～2.19 (m, 2H, CH
2); ESI-MS (m/z ,+Q): 393.0[M+Na]
+
Embodiment 5
(syn)-preparation of 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-chloro-phenyl-)-[1,3]-oxazines (HCHO-005)
Operating process just substitutes 1-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-toluidine)-1-acetone with embodiment 1 with 1-(4-chloro-phenyl-)-3-(2-thienyl)-3-(4-chloroanilino)-1-acetone, collect R
fThe component of ≈ 0.30, the white powder solid, mp:88～90 ℃, yield 55.6%;
1H-NMR (CDCl
3, 400MHz) δ: 7.36～7.24 (m, 9H, Ar-H), 7.11～7.06 (m, 2H, 2 * Ar
Thiophene-H), 5.13 (dd, J
1=1.2Hz, J
2=11.6Hz, 1H, CHO), 5.05 (d, J=10.0Hz, 2H, OCH
2N), 4.86 (dd, J
1=2.4Hz, J
2=11.6Hz, 1H, CHN), 2.26 (qd, J
1=5.6Hz, J
2=11.6Hz, J
3=14.0Hz, 1H, CH
2), 2.16 (dt, J
1=2.0Hz, J
2=14.0Hz, 1H, CH
2); ESI-MS (m/z ,+Q): 412.0[M+Na]
+
Embodiment 6
(anti)-preparation of 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-chloro-phenyl-)-[1,3]-oxazines (HCHO-006)
Operating process is collected R with embodiment 5
fThe component of ≈ 0.15, the white powder solid, mp:106～108 ℃, yield 20.6%;
1H-NMR (CDCl
3, 400MHz) δ: 7.36～7.33 (m, 4H, 4 * Ar-H), 7.16～7.13 (m, 3H, 2 * Ar-H+Ar
Thiophene-H), 7.04 (d, J=8.8Hz, 2H, 2 * Ar-H), 6.87～6.85 (m, 2H, 2 * Ar
Thiophene-H), 5.12 (d, J=10.0Hz, 1H, OCH
2N), 4.82 (d, J=15.2Hz, CHO), 4.79 (d, J=10.0Hz, 1H, OCH
2N), 4.73 (dd, J
1=5.6Hz, J
2=8.4Hz, 1H, CHN), 2.24～2.19 (m, 2H, CH
2); ESI-MS (m/z ,+Q): 390.0[M+H]
+
Embodiment 7
(syn)-preparation of 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-fluorophenyl)-[1,3]-oxazines (HCHO-007)
Operating process just substitutes 1-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-toluidine)-1-acetone with embodiment 1 with 1-(4-fluorophenyl)-3-(2-thienyl)-3-(4-chloroanilino)-1-acetone, collect R
fThe component of ≈ 0.30, the white powder solid, mp:104～106 ℃, yield 53.8%;
1H-NMR (CDCl
3, 400MHz) δ: 7.36～7.24 (m, 7H, Ar-H), 7.11～7.02 (m, 4H, Ar-H+Ar
Thiophene-H), 5.12 (dd, J
1=1.2Hz, J
2=11.6Hz, 1H, CHO), 5.06 (d, J=11.6Hz, 2H, OCH
2N), 4.87 (dd, J
1=2.4Hz, J
2=11.6Hz, 1H, CHN), 2.28 (qd, J
1=5.6Hz, J
2=11.6Hz, J
3=14.0Hz, 1H, CH
2), 2.16 (dt, J
1=2.0Hz, J
2=14.0Hz, 1H, CH
2); ESI-MS (m/z ,+Q): 374.0[M+H]
+
Embodiment 8
(anti)-preparation of 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-fluorophenyl)-[1,3]-oxazines (HCHO-008)
Operating process is collected R with embodiment 7
fThe component of ≈ 0.15, the white powder solid, mp:74～76 ℃, yield 17.5%;
1H-NMR (CDCl
3, 400MHz) δ: 7.42～7.38 (m, 2H, 2 * Ar-H), 7.17～7.14 (m, 3H, 2 * Ar-H+Ar
Thiophene-H), 7.09～7.04 (m, 4H, 4 * Ar-H), 6.88～6.86 (m, 2H, 2 * Ar
Thiophene-H), 5.13 (d, J=10.0Hz, 1H, OCH
2N), 4.82 (dd, J
1=5.6Hz, J
2=8.8Hz, CHO), 4.81 (d, J=10.0Hz, 1H, OCH
2N), 4.73 (dd, J
1=4.4Hz, J
2=9.6Hz, 1H, CHN), 2.31～2.20 (m, 2H, CH
2); ESI-MS (m/z ,+Q): 374.0[M+H]
+
Embodiment 9
(syn)-preparation of 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-nitrophenyl)-[1,3]-oxazines (HCHO-009)
Operating process just substitutes 1-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-toluidine)-1-acetone with embodiment 1 with 1-(4-nitrophenyl)-3-(2-thienyl)-3-(4-chloroanilino)-1-acetone, collect R
fThe component of ≈ 0.25, the white powder solid, mp:126～128 ℃, yield 57.0%;
1H-NMR (CDCl
3, 400MHz) δ: 8.23 (d, J=8.8Hz, 2H, 2 * Ar-H), 7.53 (d, J=8.8Hz, 2H, 2 * Ar-H), 7.38～7.36 (m, 1H, Ar
Thiophene-H), 7.31 (d, J=8.8Hz, 2H, 2 * Ar-H), 7.25 (d, J=8.8Hz, 2H, 2 * Ar-H), 7.13～7.10 (m, 2H, Ar
Thiophene-H), 5.17 (dd, J
1=1.2Hz, J
2=12.0Hz, 1H, CHO), 5.08 (d, J=12.0Hz, 2H, OCH
2N), 5.00 (t, J=6.4Hz, 1H, CHN), 2.24～2.21 (m, 2H, CH
2); ESI-MS (m/z ,+Q): 401.0[M+H]
+
Embodiment 10
(anti)-preparation of 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-nitrophenyl)-[1,3]-oxazines (HCHO-010)
Operating process is collected R with embodiment 9
fThe component of ≈ 0.15, the white powder solid, mp:136～138 ℃, yield 26.9%;
1H-NMR (CDCl
3, 400MHz) δ: 8.24 (d, J=8.8Hz, 2H, 2 * Ar-H), 7.60 (d, J=8.8Hz, 2H, 2 * Ar-H), 7.16 (d, J=8.8Hz, 2H, 2 * Ar-H), 7.16～7.14 (m, 1H, Ar
Thiophene-H), 7.03 (d, J=8.8Hz, 2H, 2 * Ar-H), 6.88～6.85 (m, 2H, Ar
Thiophene-H), 5.15 (d, J=10.0Hz, 1H, OCH
2N), 4.90～4.83 (m, 2H, CHO+CHN), 4.82 (d, J=10.0Hz, 1H, OCH
2N), 2.37～2.15 (m, 2H, CH
2); ESI-MS (m/z ,+Q): 401.0[M+H]
+
Embodiment 11～17
Operating process is with embodiment 1, just will be just with 1-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-toluidine)-1-acetone with corresponding 1,3-diaryl-3-aryl amine-1-acetone compounds substitutes, formaldehyde substitutes with corresponding aldehyde compound, can prepare following compound:
Embodiment 18 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 dextran 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
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 the day before yesterday, 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 with the plain detection kit of luciferase, assess the agonist activity of compound androgen receptor with this.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 the day before yesterday, 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 sees Table 1:
Table 13,4, the reporter gene expression detected result of 6-triaryl-[1,3]-oxazine 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 than the antagonistic activity of syn configuration.
Test result shows, 3,4,6-triaryl-[1,3]-the oxazine 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 lack partly that syndrome, osteoporosis, muscle wasting, femal sexual function are complete, 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. a class 3,4,6-triaryl-[1,3]-oxazine compounds (I) is characterized in that it is the compound with following chemical structure of general formula:
R in the formula
1, R
2, R
3, R
4Expression H, halogen, C
1～C
12Alkyl, C
l～C
12Alkoxyl group, nitro, cyano group, carboxyl, hydroxyl, CF
3R
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 represents aryl, substituted aryl; R
5Expression H, C
1～C
12Alkyl, C
3～C
7Cycloalkyl, C
6～C
12Aryl, furyl, thienyl, pyridyl, carboxyl.
2. as claimed in claim 13,4,6-triaryl-[1,3]-oxazine compounds is characterized in that, described compound structure type is cis (syn) or trans (anti) or cis and trans arbitrary proportion mixture.
3. as claim 1～2 described 3,4,6-triaryl-[1,3]-oxazine compounds, it is characterized in that, described compound preferably from: 3,6-two (4-aminomethyl phenyl)-4-(2-thienyl)-[1,3]-oxazines, 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-aminomethyl phenyl)-[1,3]-oxazines, 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-chloro-phenyl-)-[1,3]-oxazines, 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-fluorophenyl)-[1,3]-oxazines, 3-(4-chloro-phenyl-)-4-(2-thienyl)-6-(4-nitrophenyl)-[1,3]-oxazines, 2-phenyl-3-(4-p-methoxy-phenyl)-4-phenyl-6-(4-cyano-phenyl)-[1,3]-oxazines, 2-methyl-3-(4-hydroxy phenyl)-4-phenyl-6-(4-trifluoromethyl)-[1,3]-oxazines, 2-carboxyl-3-(4-aminomethyl phenyl)-4-(2-furyl)-6-(4-chloro-phenyl-)-[1,3]-oxazines, 2-(2-thienyl)-3-(4-aminomethyl phenyl)-4-(2-furyl)-6-(4-chloro-phenyl-)-[1,3]-oxazines, 3-(4-chloro-phenyl-)-4-(3-pyridyl)-6-(4-chloro-phenyl-)-[1,3]-oxazines, 2-(2-furyl)-3-(4-bromophenyl)-4-(4-chloro-phenyl-)-6-(4-p-methoxy-phenyl)-[1,3]-oxazines, 2-cyclohexyl-3-(4-chloro-phenyl-)-4-(4-nitrophenyl)-6-(4-carboxyl phenyl)-[1,3]-oxazines.
4. as described in the claim 1～3 3,4, the preparation method of 6-triaryl-[1,3]-oxazine compounds, it is characterized in that, with 1,3-diaryl-3-aryl amine-1-acetone compounds (1) is a starting raw material, reduces through reductive agent in suitable solvent, get 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 aldehyde compound R
5CHO or its hemiacetal or acetal cyclization, get 3,4, the syn of 6-triaryl-[1,3]-oxazine compounds (I) and anti mixture (3), then through recrystallization or column chromatographic isolation and purification step, obtain 3,4 respectively, 6-triaryl-[1,3] the syn isomer of-oxazine compounds (I) and anti isomer, its chemical equation is as follows:
5. as claimed in claim 43,4, the preparation method of 6-triaryl-[1,3]-oxazine 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 ethyl 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; 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; 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]-oxazine compounds is characterized in that the ring-closure reaction solvent for use is: water, C
3-8Aliphatic ketone, 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, acetonitrile or pyridine, reaction can be carried out in single solvent, also can carry out in the mixture of above-mentioned two kinds of solvents, and the mixed solvent volume ratio is 1: 0.1～10; Aldehyde compound can be used R
5CHO or itself and C
1-6The formed hemiacetal of Fatty Alcohol(C12-C14 and C12-C18) or itself and C
1-6Formed acetal of Fatty Alcohol(C12-C14 and C12-C18) or R
5CHO self-polymerization thing; Aldehyde compound and l, 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-20 ℃～150 ℃; Reaction times is 1 hour～48 hours.
7. as claimed in claim 43,4, the preparation method of 6-triaryl-[1,3]-oxazine compounds is characterized in that the purification procedures method therefor is: recrystallization or column chromatography, wherein, recrystallization solvent can be used C
1～C
6Fatty Alcohol(C12-C14 and C12-C18), ethers, sherwood oil, C
3-8Aliphatic ketone, 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, recrystallization can carry out in single solvent, also can carry out in mixed solvent, and the mixed solvent volume ratio is 1: 0.1～10; The elutriant of column chromatography for separation can be used sherwood oil/chloroform, petrol ether/ethyl acetate mixed solution, and its proportioning is 1～99/99～1 (v/v).
8. pharmaceutical composition, each is described 3,4 as claim 1～3 for one or more that comprise the treatment significant quantity, 6-triaryl-[1,3]-oxazine 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.
Claim 1～3 each described 3,4,6-triaryl-[1,3]-oxazine 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.
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