CN101250136A - 1,3-diaryl-3-aryl amidine-1-acetoxime compounds, preparation method and use thereof - Google Patents
1,3-diaryl-3-aryl amidine-1-acetoxime compounds, preparation method and use thereof Download PDFInfo
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Abstract
The invention relates to a non-steroidal androgen receptor modulator compound containing 1, 3-diaryl-3-aromatic amine-1-acetoxime compound (I), or relative medical acceptable salt and a relative preparation method. The invention also relates to a drug compound of 1, 3-diaryl-3-aromatic amine-1-acetoxime compound (I) and relative medical acceptable salt. The1, 3-diaryl-3-aromatic amine-1-acetoxime compound (I) or relative medical acceptable salt has androgen receptor antagonistic activity, therefore, the compound can be used to prepare the non-steroidal drug for preventing or/treating prostatic hyperplasia, prostate cancer, hirsutism, serious androgen dependence alopecia and acne or the like.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to 1,3-diaryl-3-aryl amine-1-acetoxime compounds (I) and preparation method thereof, pharmaceutical composition and in the preparation prevention or/and the purposes in the medicine of symptom such as treatment hyperplasia of prostate, prostate cancer, hirsutism, the dependent form alopecia of severe male sex hormone or acne or disease.
(R in the formula
1, R
2, R
3, R
4Expression H, halogen, C
1～C
12Alkyl, C
3～C
7Cycloalkyl, C
6～C
12Aryl, C
1～C
12Alkoxyl group, C
6～C
12Aryloxy, C
1～C
12Alkylthio, C
6～C
12Arylthio, nitro, cyano group, carboxyl, hydroxyl, CF
3, NR
5R
6R
5, R
6Expression 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 represents phenyl, substituted-phenyl, furyl, substituted furan base, thienyl, substituted thiophene base, pyridyl, substituted pyridinyl)
Background technology
Male sex hormone 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, and it is by (AndrogenReceptor is AR) in conjunction with performance important physical function with androgen receptor.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 nonsteroidal androgen antagonist medicine has than highly selective AR, to the effect that other steroid receptor can not produce hormonelike or hormone antagonist, therefore toxic side effect is less in clinical application.Yet, at present there are many problems to be solved that have in the androgen antagonist medicine of listing: at first, can occur various side effects such as gastrointestinal discomfort after patient takes, feel sick, vomiting, insomnia, weak, headache, anxiety, blurred vision, hyposexuality and hepatotoxicity etc.; 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 ", show as after medication for some time originally that repressed prostate specific antigen level rises rapidly again, gross tumor volume increases, can only withdrawal or other androgen antagonist medicine 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.Therefore, press for the 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 Nonsteroic androgen acceptor regulators or its pharmacy acceptable salt of diaryl-3-aryl amine-1-acetone oximes (I) chemical structure;
Another object of the present invention is to provide 1, the preparation method of 3-diaryl-3-aryl amine-1-acetoxime compounds (I);
Another purpose of the present invention is to provide and comprises 1, the pharmaceutical composition of 3-diaryl-3-aryl amine-1-acetoxime compounds (I) or its pharmacy acceptable salt;
A further object of the present invention is to provide 1,3-diaryl-3-aryl amine-1-acetoxime compounds (I) or its pharmacy acceptable salt 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 acne or disease.
Provided by the invention 1, the chemical structure of 3-diaryl-3-aryl amine-1-acetoxime non-steroid androgen receptor function regulator compound or its pharmacy acceptable salt is shown in I:
(R in the formula
1, R
2, R
3, R
4Expression H, halogen, C
1～C
12Alkyl, C
3～C
7Cycloalkyl, C
6～C
12Aryl, C
1～C
12Alkoxyl group, C
6～C
12Aryloxy, C
1～C
12Alkylthio, C
6～C
12Arylthio, nitro, cyano group, carboxyl, hydroxyl, CF
3, NR
5R
6R
5, R
6Expression 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 represents phenyl, substituted-phenyl, furyl, substituted furan base, thienyl, substituted thiophene base, pyridyl, substituted pyridinyl)
For of the present invention 1,3-diaryl-3-aryl amine-1-acetoxime compounds (I) or its pharmacy acceptable salt, when having chiral carbon in the molecule, it is raceme or optically active body.
Provided by the invention 1,3-diaryl-3-aryl amine-available following method of 1-acetoxime compounds (I) prepares:
With acetophenone derivs (1), aromatic aldehyde (2) and aromatic amine (3) is raw material, through acid catalysis, the Mannich condensation reaction takes place in suitable solvent, gets corresponding Mannich alkali salt; With the appropriate bases neutralization, get Mannich alkali (4); Gained intermediate 4 in suitable solvent and alkaline condition under with the oxammonium hydrochloride condensation, 1,3-diaryl-3-aryl amine-1-acetoxime compounds (I); I again with suitable sour salify, promptly get 1,3-diaryl-3-aryl amine-1-acetone oximate.
Wherein, Mannich condensation reaction solvent for use is C
1～C
6Fatty Alcohol(C12-C14 and C12-C18), methylene dichloride, chloroform, ethyl acetate, benzene, normal heptane, toluene, acetonitrile, tetrahydrofuran (THF), its preferred solvent are C
1～C
6Fatty Alcohol(C12-C14 and C12-C18), tetrahydrofuran (THF); Acid catalyst is protonic acid (as: hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc.) or Lewis acid (as: BF
3-Et
2O, TiCl
4, SnCl
4, AlCl
3, FeCl
3Deng), its preferred acid catalyzer is hydrochloric acid, Hydrogen bromide, BF
3-Et
2O, TiCl
4The molar feed ratio of acid catalyst and acetophenone derivs (1) is 0.001～0.5: 1.0, and preferred molar feed ratio is 0.01～0.1: 1.0; Temperature of reaction is room temperature～150 ℃, and preferable reaction temperature is room temperature or back flow reaction; Reaction times is 1～128 hour, and the preferred reaction time is 24～48 hours.
Mannich alkali (4) is water, C with oxammonium hydrochloride condensation reaction solvent for use
1～C
6Fatty Alcohol(C12-C14 and C12-C18), methylene dichloride, chloroform, ethyl acetate, benzene, normal heptane, toluene, acetonitrile, tetrahydrofuran (THF), its preferred solvent are water, C
1～C
6Fatty Alcohol(C12-C14 and C12-C18), acetonitrile; Used alkali is basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, trimethylamine class or quaternary ammonium bases (as: triethylamine, Tributylamine, trioctylamine, pyridine, N, N-dimethyl-α-Ben Yian, TBAH), preferred catalyst is: lithium hydroxide, sodium bicarbonate, salt of wormwood, triethylamine; The molar feed ratio of alkali and oxammonium hydrochloride is 0.5～2.0: 1.0, and preferred molar feed ratio is 1.0～1.5: 1.0; Mannich alkali (4) is 1.0: 1.0～2.0 with the molar feed ratio of oxammonium hydrochloride, and preferred molar feed ratio is 1.0: 1.0～1.5; Temperature of reaction is room temperature～150 ℃, and preferable reaction temperature is room temperature or back flow reaction; Reaction times is 0.1～48 hour, and the preferred reaction time is 2～12 hours.
Provided by the invention 1,3-diaryl-3-aryl amine-1-acetoxime compounds (I) can obtain acceptable salt on its pharmacology by conventional salifiable method pharmaceutically with any suitable acid, and described acid is mineral acid (as: hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid etc.); Organic acid (as: formic acid, acetate, propionic acid, phenylformic acid, toxilic acid, fumaric acid, succsinic acid, tartrate, citric acid etc.; Alkylsulphonic acid is as methylsulphonic acid, ethylsulfonic acid etc.; Aryl sulfonic acid is as Phenylsulfonic acid, tosic acid etc.) all can use.
Pharmaceutical composition provided by the invention comprise the treatment significant quantity one or more 1,3-diaryl-3-aryl amine-1-acetoxime compounds (I) or its pharmacy acceptable salt, this pharmaceutical composition can further contain one or more pharmaceutically acceptable carrier or vehicle.
Its ideal ratio of pharmaceutical composition provided by the present invention is, 1,3-diaryl-3-aryl amine-1-acetoxime compounds (I) or its pharmacy acceptable salt 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 1,3-diaryl-3-aryl amine-1-acetoxime compounds (I) or its pharmacy acceptable salt have the AR 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, the dependent form alopecia of severe male sex hormone or acne 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.
The preparation of embodiment 1 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetoxime
Add phenyl aldehyde 1.06 grams (0.01mol), 4-chloroaniline 1.28 gram (0.01mol) and dehydrated alcohol 18ml in reaction flask, stirring at room added 4-nitro-acetophenone 1.65 gram (0.01mol) and catalytic amount concentrated hydrochloric acids, the stirring at room reaction after 10 minutes; The solid that suction filtration is separated out, and use absolute ethanol washing.The gained solid suspension is used saturated NaHCO in 20ml ethanol
3The aqueous solution is neutralized to alkalescence, and suction filtration, a small amount of absolute ethanol washing filter cake, crude product get buff powder solid 3.43 grams, yield 83% through ethanol/water mixed solvent (volume ratio 1: 1) recrystallization.
Above-mentioned solid 1.9 grams (5mmol) and ethanol 20ml are added in the reaction flask, after stirring, add oxammonium hydrochloride 0.56 gram (8mmol), salt of wormwood 1.1 gram (8mmol) and deionized water 10ml successively, temperature rising reflux stirring reaction 5 hours, after reaction finished, room temperature left standstill, the solid that filtration is separated out, use the ethanol/water recrystallization, get yellow crystal 1.41 grams, yield 70.91%;
1H-NMR (400MHz, CDCl
3) δ: 8.19 (d, 2H, J=9.2Hz), 7.66 (d, 2H, J=9.2Hz), 7.36～7.21 (m, 5H), 7.00 (d, 2H, J=8.8Hz), 6.39 (d, 2H, J=8.8Hz), 4.67 (t, 1H, J=5.2Hz), 3.67～3.58 (m, 1H), 3.08 (dd, 1H, J
1=13.2Hz, J
2=5.2Hz); ESI-MS m/z:418.8 (M
++ Na).
The preparation of embodiment 2 1-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-chloroanilino)-1-acetoxime
Operating process is that phenyl aldehyde is substituted with 2-thiophene phenol formaldehyde with embodiment 1, and the 4-nitro-acetophenone substitutes with the 4-methyl acetophenone, gets white crystals, yield 85.6%; Mp117～119 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.44 (d, 2H, J=8.4Hz), 7.19 (d, 2H, J=8Hz), 7.16 (d, 1H, J=4.4Hz), 6.99 (m, 3H), 6.92 (t, 1H, J=3.6Hz), 6.39 (d, 2H, J=8.4Hz), 4.89 (dd, 1H, J=4.4Hz), 3.69 (dd, 1H, J
1=13.6Hz, J
2=10Hz), 3.11 (dd, 1H, J
1=13.6Hz, J
2=4.4Hz), 2.38 (s, 3H); ESI-MS m/z:404.2 (M
++ H+MeOH).
The preparation of embodiment 3 1-(4-aminomethyl phenyl)-3-phenyl-3-(4-chloroanilino)-1-acetoxime
Operating process just substitutes the 4-nitro-acetophenone with embodiment 1 with the 4-methyl acetophenone, get light yellow crystallization, yield 93.4%; Mp156～158 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.48 (d, 2H, J=8.4Hz), 7.38 (d, 2H, J=6.8Hz), 7.32 (t, 2H, J=7.2Hz), 7.26～7.20 (m, 3H), 6.93 (d, 2H, J=8.8Hz), 6.28 (d, 2H, J=9.2Hz), 4.55 (dd, 1H, J
1=10.4Hz, J
2=4Hz), 3.59 (dd, 1H, J
1=13.6Hz, J
2=10.4Hz), 2.97 (dd, 1H, J
1=13.8Hz, J
2=4Hz), 2.38 (s, 3H); ESI-MS m/z:365.9 (M
++ H).
The preparation of embodiment 4 1-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetoxime
Operating process is with embodiment 1, and just that phenyl aldehyde is alternative with 2-thiophene phenol formaldehyde, the 4-nitro-acetophenone substitutes with the 4-methyl acetophenone, and the 4-chloroaniline substitutes with the 4-N-methyl-p-nitroaniline, gets yellow crystal, yield 88.0%; Mp118～120 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.95 (d, 2H, J=9.2Hz), 7.46 (d, 2H, J=8.4Hz), 7.22～6.94 (m, 5H), 6.40 (d, 2H, J=9.2Hz), 5.02 (dd, 1H, J
1=10.2Hz, J
2=4.4Hz), 3.80～3.72 (m, 1H), 3.14 (dd, 1H, J
1=13.6Hz, J
2=4Hz); ESI-MS m/z:404.3 (M
++ Na).
The preparation of embodiment 5 1-(4-fluorophenyl)-3-phenyl-3-(4-oil of mirbane amido)-1-acetoxime
The same example I of operating process is that the 4-nitro-acetophenone is substituted with the 4-fluoro acetophenone, and the 4-chloroaniline substitutes with the 4-N-methyl-p-nitroaniline, gets yellow crystal, yield 90.3%; Mp163～164 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.94 (d, 2H, J=9.2Hz), 7.54 (m, 2H), 7.33 (d, 4H, J=4.4H), 7.28 (m, 1H), 7.08 (t, 2H, J=8.8Hz), 6.35 (d, 2H, J=9.2Hz), 4.69 (dd, 1H, J
1=10.4Hz, J
2=4Hz), 3.68 (dd, 1H, J
1=10.4Hz, J
2=13.8Hz), 3.01 (dd, 1H, J
1=13.8Hz, J
2=4Hz); ESI-MS m/z:402.4 (M
++ Na).
The preparation of embodiment 6 1-(4-chloro-phenyl-)-3-phenyl-3-(4-oil of mirbane amido)-1-acetoxime
Operating process is that the 4-nitro-acetophenone is substituted with the 4-chloro-acetophenone with embodiment 1, and the 4-chloroaniline substitutes with the 4-N-methyl-p-nitroaniline, gets yellow crystal, yield 94.5%; Mp182～184 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.94 (d, 2H, J=8.8Hz), 7.49 (d, 2H, J=8.8Hz), 7.38～7.26 (m, 7H), 6.35 (d, 2H, J=8.8Hz), 4.68 (dd, 1H, J=4.4Hz), 3.69～3.64 (m, 1H), 3.00 (dd, 1H, J
1=10Hz, J
2=4.4Hz); ESI-MS m/z:418.8 (M
++ Na).
The preparation of embodiment 7 1-(4-chloro-phenyl-)-3-phenyl-3-(4-chloroanilino)-1-acetoxime
Operating process just substitutes the 4-nitro-acetophenone with embodiment 1 with the 4-chloro-acetophenone, get white crystals, yield 84.7%; Mp122～124 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.47 (d, 2H, J=9.2Hz), 7.37～7.22 (m, 7H), 6.96 (d, 2H, J=8.8Hz), 6.32 (d, 2H, J=8.8Hz), 4.57 (dd, 1H, J
1=10Hz, J
2=4.4Hz), 3.61～3.55 (dd, 1H, J
1=13.6Hz, J
2=10Hz), 2.97 (dd, 1H, J
1=13.6Hz, J
2=4.8Hz); ESI-MS m/z:386.3 (M
++ H).
The preparation of embodiment 8 1-(4-fluorophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetoxime
Operating process just substitutes the 4-nitro-acetophenone with embodiment 1 with the 4-fluoro acetophenone, get white crystals, yield 97.8%; Mp118～120 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.52 (dd, 2H, J
1=9.2Hz, J
2=5.6Hz), 7.36 (d, 2H, J=8.4Hz), 7.31 (t, 2H, J=7.2Hz), 7.24 (d, 2H, J=8.8Hz), 7.06 (t, 2H, J=8.8Hz), 6.96 (d, 2H, J=8.8Hz), 6.31 (d, 2H, J=8.8Hz), 4.56 (dd, 1H, J
1=6Hz, J
2=8Hz), 3.62～3.56 (m, 1H), 3.59 (dd, 1H, J
1=13.6Hz, J
2=9.6Hz), 2.97 (dd, 1H, J
1=13.4Hz, J
2=4.4Hz); ESI-MS m/z:369.9 (M
++ H).
The preparation of embodiment 9 1-(4-chloro-phenyl-)-3-(2-thienyl)-3-(4-chloroanilino)-1-acetoxime
Operating process is that phenyl aldehyde is substituted with 2-thiophene phenol formaldehyde with embodiment 1, and the 4-nitro-acetophenone substitutes with the 4-chloro-acetophenone, gets colorless oil, yield 36.9%; Mp118～120 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.44 (d, 2H, J=8.4Hz), 7.33 (d, 2H, J=8.4Hz), 7.16 (dd, 1H, J
1=4.8Hz, J
2=1.2Hz), 7.01 (d, 2H, J=8.8Hz), 6.96 (d, 1H, J=3.6Hz), 6.91 (m, 1H), 6.42 (d, 2H, J=8.8Hz), 4.92 (dd, 1H, J
1=9.6Hz, J
2=5.2Hz), 4.68 (s, 1H), 3.66 (dd, 1H, J
1=13.6Hz, J
2=9.6Hz), 3.10 (dd, 1H, J
1=13.8Hz, J
2=5.2Hz); ESI-MS m/z:392.3 (M
++ H).
The preparation of embodiment 10 1-(4-chloro-phenyl-)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetoxime
Operating process is with embodiment 1, and just that phenyl aldehyde is alternative with 2-thiophene phenol formaldehyde, the 4-nitro-acetophenone substitutes with the 4-chloro-acetophenone, and the 4-chloroaniline substitutes with the 4-N-methyl-p-nitroaniline, gets yellow crystal, yield 79.7%; Mp158～160 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.99 (d, 2H, J=9.2Hz), 7.47 (d, 2H, J=8.4Hz), 7.35 (d, 2H, J=8.4Hz), 7.21～6.93 (m, 3H), 6.46 (d, 2H, J=9.2Hz), 5.05 (dd, 1H, J
1=9.8Hz, J
2=4.8Hz), 3.77～3.72 (m, 1H), 3.14 (dd, 1H, J
1=13.6Hz, J
2=4.8Hz); ESI-MS m/z:402.9 (M
++ H).
The preparation of embodiment 111-(4-fluorophenyl)-3-(2-thienyl)-3-(4-chloroanilino)-1-acetoxime
Operating process is that phenyl aldehyde is substituted with 2-thiophene phenol formaldehyde with embodiment 1, and the 4-nitro-acetophenone substitutes with the 4-fluoro acetophenone, gets colorless oil, yield 79.3%;
1H-NMR (400MHz, CDCl
3) δ: 8.40 (brs, 1H), 7.49 (m, 2H), 7.15 (dd, 1H, J
1=1.2Hz, J
2=4.8Hz), 7.05 (m, 2H), 7.02 (d, 2H, J=8.8Hz), 6.97 (d, 1H, J=3.2Hz), 6.91 (dd, 1H, J
1=3.2Hz, J
2=4.8Hz), 6.42 (d, 2H, J=8.8Hz), 4.93 (dd, 1H, J
1=9.6Hz, J
2=5.2Hz), 4.70 (brs, 1H), 3.67 (dd, 1H, J
1=13.4Hz, J
2=9.6Hz), 3.10 (dd, 1H, J
1=10.6Hz, J
2=5.2Hz); ESI-MS m/z:375.9 (M
++ H).
The preparation of embodiment 12 1-(4-fluorophenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetoxime
Operating process is with embodiment 1, and just that phenyl aldehyde is alternative with 2-thiophene phenol formaldehyde, the 4-nitro-acetophenone substitutes with the 4-fluoro acetophenone, and the 4-chloroaniline substitutes with the 4-N-methyl-p-nitroaniline, gets yellow crystal, yield 77.2%; Mp128～130 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.99 (d, 2H, J=9.2Hz), 7.52 (dd, 2H, J
1=8.8Hz, J
2=5.2Hz), 7.20 (d, 1H, J=5.2Hz), 7.07 (t, 2H, J=8.4Hz), 7.01 (d, 1H, J=3.6Hz), 6.94 (dd, 1H, J
1=4.8Hz, J
2=3.6Hz), 6.46 (d, 2H, J=9.2Hz), 5.05 (dd, 1H, J
1=9.8Hz, J
2=4.4Hz), 3.76 (dd, 1H, J
1=13.6Hz, J
2=10Hz), 3.15 (dd, 1H, J
1=13.6Hz, J
2=4.8Hz); ESI-MS m/z:386.4 (M
++ H).
The preparation of embodiment 13 1-(4-fluorophenyl)-3-(2-furyl)-3-(4-oil of mirbane amido)-1-acetoxime
Operating process is with embodiment 1, and just that phenyl aldehyde is alternative with 2 furan carboxyaldehyde, the 4-nitro-acetophenone substitutes with the 4-fluoro acetophenone, and the 4-chloroaniline substitutes with the 4-N-methyl-p-nitroaniline, gets yellow crystal, yield 86.5%; ESI-MS m/z:370.4 (M
++ H).
The preparation of embodiment 14 1-(4-chloro-phenyl-)-3-(2-furyl)-3-(4-oil of mirbane amido)-1-acetoxime
Operating process is with embodiment 1, and just that phenyl aldehyde is alternative with 2 furan carboxyaldehyde, the 4-nitro-acetophenone substitutes with the 4-chloro-acetophenone, and the 4-chloroaniline substitutes with the 4-N-methyl-p-nitroaniline, gets yellow crystal, yield 87.3%; ESI-MS m/z:386.8 (M
++ H).
The preparation of embodiment 15 1-(4-bromophenyl)-3-(2-furyl)-3-(4-oil of mirbane amido)-1-acetoxime
Operating process is with embodiment 1, and just that phenyl aldehyde is alternative with 2 furan carboxyaldehyde, the 4-nitro-acetophenone substitutes with the 4-bromoacetophenone, and the 4-chloroaniline substitutes with the 4-N-methyl-p-nitroaniline, gets yellow crystal, yield 91.6%; ESI-MS m/z:431.3 (M
++ H).
The preparation of embodiment 16 1-(4-fluorophenyl)-3-(2-furyl)-3-(4-chloro-3-oil of mirbane amido)-1-acetoxime
Operating process is with embodiment 1, and just that phenyl aldehyde is alternative with 2 furan carboxyaldehyde, the 4-nitro-acetophenone substitutes with the 4-fluoro acetophenone, and the 4-chloroaniline substitutes with 3-nitro-4-chloroaniline, gets yellow crystal, yield 78.9%; ESI-MSm/z:404.8 (M
++ H).
The preparation of embodiment 17 1-(4-chloro-phenyl-)-3-(2-furyl)-3-(4-chloro-3-oil of mirbane amido)-1-acetoxime
Operating process is with embodiment 1, and just that phenyl aldehyde is alternative with 2 furan carboxyaldehyde, the 4-nitro-acetophenone substitutes with the 4-chloro-acetophenone, and the 4-chloroaniline substitutes with 3-nitro-4-chloroaniline, gets yellow crystal, yield 82.6%; ESI-MSm/z:421.3 (M
++ H).
The preparation of embodiment 18 1-(4-bromophenyl)-3-(2-furyl)-3-(4-chloro-3-oil of mirbane amido)-1-acetoxime
Operating process is with embodiment 1, and just that phenyl aldehyde is alternative with 2 furan carboxyaldehyde, the 4-nitro-acetophenone substitutes with the 4-bromoacetophenone, and the 4-chloroaniline substitutes with 3-nitro-4-chloroaniline, gets yellow crystal, yield 80.7%; ESI-MSm/z:465.6 (M
++ H).
The test of embodiment 19 receptors bind vigor
With DMSO is solvent, the gradient solution of preparation DHT and each compound of gained, DHT concentration is followed successively by 0,0.3,1,3,10,30,100nM, each compound concentration is followed successively by 0,0.128,0.64,3.2,16,80,400,2000nM, adds each gradient DHT of 5 μ l or testing compound solution respectively to each hole of comb; Androgen receptor protein is added damping fluid (the 25mM Na that is furnished with 1 μ g/ μ l Trypsin inhibitor,Trasylol (Aprotinin) and bright Trypsin inhibitor,Trasylol proteinase inhibitor such as (Leupeptin) in advance
3PO
4, 10% glycerine (Glycerol), 10mM NaMoO
4, 10mM KF, pH7.5) in, add final concentration and be 5nM [
3H] DHT, behind the thorough mixing, add in the comb by the amount of every hole 195 μ l rapidly, 4 ℃ of overnight incubation, hatch finish after, in the every hole of comb, add 50 μ l hydroxyapatite (HA) solution (25%HA, 25mM Na
3PO
4, pH7.4), concussion was evenly hatched 10 minutes, shook once in per therebetween three minutes, centrifugal 3 minutes of 2500rpm siphons away supernatant liquor, keep precipitation, every hole adds the above-mentioned damping fluid of 200 μ l, avoids the vibration precipitation as far as possible, recentrifuge 3 minutes siphons away supernatant liquor, keeps precipitation, repeated centrifugation once siphons away supernatant liquor, keeps precipitation, every hole adds 300 μ l scintillation solutions, and the concussion mixing is used
Reading, target compound and receptors bind vigor test result see Table 1
Table 11,3-diaryl-3-aryl amine-1-acetoxime compounds combines active result with AR
| Compound | IC 50(nM) | Compound | IC 50(nM) | |
| DHT | 3.7 | oxime-8 | 112.1 | |
| oxime-2 | 174.9 | oxime-9 | 10074.0 | |
| oxime-4 | 152.7 | oxime-10 | 8098.0 | |
| oxime-5 | 1570.0 | oxime-11 | NA | |
| oxime-6 | 1956.0 | oxime-12 | NA | |
| oxime-7 | 61.7 |
Above-mentioned test result shows, oxime-2, oxime-4, oxime-7, oxime-8 show in androgen receptor competitiveness is tested in conjunction with vigor preferably in conjunction with active, having exploitation becomes the potentiality of novel androgen receptor function regulator, can be used for preparing 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 acne or disease.
Claims (10)
1. a class 1,3-diaryl-3-aryl amine-1-acetoxime compounds (I) with and pharmacy acceptable salt
(R in the formula
1, R
2, R
3, R
4Expression H, halogen, C
1～C
12Alkyl, C
3～C
7Cycloalkyl, C
6～C
12Aryl, C
1～C
12Alkoxyl group, C
6～C
12Aryloxy, C
1～C
12Alkylthio, C
6～C
12Arylthio, nitro, cyano group, carboxyl, hydroxyl, CF
3, NR
5R
6R
5, R
6Expression 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 represents phenyl, substituted-phenyl, furyl, substituted furan base, thienyl, substituted thiophene base, pyridyl, substituted pyridinyl).
2. compound according to claim 1 or its pharmacy acceptable salt is characterized in that, when having chiral carbon in the molecule, described compound is raceme or optically active body.
3. according to the described compound of claim 1～2 or its pharmacy acceptable salt, it is characterized in that described compound is: 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetoxime, 1-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-chloroanilino)-1-acetoxime, 1-(4-aminomethyl phenyl)-3-phenyl-3-(4-chloroanilino)-1-acetoxime, 1-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetoxime, 1-(4-fluorophenyl)-3-phenyl-3-(4-oil of mirbane amido)-1-acetoxime, 1-(4-chloro-phenyl-)-3-phenyl-3-(4-oil of mirbane amido)-1-acetoxime, 1-(4-chloro-phenyl-)-3-phenyl-3-(4-chloroanilino)-1-acetoxime, 1-(4-fluorophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetoxime, 1-(4-chloro-phenyl-)-3-(2-thienyl)-3-(4-chloroanilino)-1-acetoxime, 1-(4-chloro-phenyl-)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetoxime, 1-(4-fluorophenyl)-3-(2-thienyl)-3-(4-chloroanilino)-1-acetoxime, 1-(4-fluorophenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetoxime, 1-(4-fluorophenyl)-3-(2-furyl)-3-(4-oil of mirbane amido)-1-acetoxime, 1-(4-chloro-phenyl-)-3-(2-furyl)-3-(4-oil of mirbane amido)-1-acetoxime, 1-(4-bromophenyl)-3-(2-furyl)-3-(4-oil of mirbane amido)-1-acetoxime, 1-(4-fluorophenyl)-3-(2-furyl)-3-(4-chloro-3-oil of mirbane amido)-1-acetoxime, 1-(4-chloro-phenyl-)-3-(2-furyl)-3-(4-chloro-3-oil of mirbane amido)-1-acetoxime, 1-(4-bromophenyl)-3-(2-furyl)-3-(4-chloro-3-oil of mirbane amido)-1-acetoxime, 1-(4-nitrophenyl)-3-phenyl-3-(4-nitro-3-trifluoromethylbenzene amido)-1-acetoxime, 1-(4-nitrophenyl)-3-(2-thienyl)-3-(4-nitro-3-trifluoromethylbenzene amido)-1-acetoxime, 1-(4-nitrophenyl)-3-(2-furyl)-3-(4-nitro-3-trifluoromethylbenzene amido)-1-acetoxime, 1-(4-chloro-phenyl-)-3-phenyl-3-(4-nitro-3-trifluoromethylbenzene amido)-1-acetoxime, 1-(4-chloro-phenyl-)-3-(2-thienyl)-3-(4-nitro-3-trifluoromethylbenzene amido)-1-acetoxime, 1-(4-chloro-phenyl-)-3-(2-furyl)-3-(4-nitro-3-trifluoromethylbenzene amido)-1-acetoxime.
4. according to each described compound of claim 1～3 or its pharmacy acceptable salt, it is characterized in that, described pharmacy acceptable salt is 1, the salt of 3-diaryl-3-aryl amine-1-acetoxime compounds (I) and hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, formic acid, acetate, propionic acid, phenylformic acid, toxilic acid, fumaric acid, succsinic acid, tartrate, citric acid, methylsulphonic acid, ethylsulfonic acid, Phenylsulfonic acid, tosic acid.
5. according to the described compound of claim 1～4 or its pharmacy acceptable salt, it is characterized in that, the preparation method of described compound, comprise: with acetophenone derivs (1), aromatic aldehyde (2) and aromatic amine (3) is raw material, in suitable solvent through acid catalysis, the Mannich condensation reaction takes place, and gets corresponding Mannich alkali salt; With appropriate bases neutralization, Mannich alkali (4), gained intermediate 4 in suitable solvent and under the alkaline condition with the oxammonium hydrochloride condensation, 1,3-diaryl-3-aryl amine-1-acetoxime compounds (I); I again with suitable sour salify, promptly get 1,3-diaryl-3-aryl amine-1-acetone oximate, its chemical equation is as follows:
6. according to claim 51, the preparation method of 3-diaryl-3-aryl amine-1-acetoxime compounds (I) or its pharmacy acceptable salt is characterized in that Mannich condensation reaction solvent for use is C
1～C
6Fatty Alcohol(C12-C14 and C12-C18), methylene dichloride, chloroform, ethyl acetate, benzene, normal heptane, toluene, acetonitrile, tetrahydrofuran (THF); Acid catalyst is protonic acid or Lewis acid; The molar feed ratio of acid catalyst and acetophenone derivs (1) is 0.001～0.5: 1.0; Temperature of reaction is room temperature～150 ℃; Reaction times is 1～128 hour.
7. according to claim 51, the preparation method of 3-diaryl-3-aryl amine-1-acetoxime compounds (I) or its pharmacy acceptable salt is characterized in that, Mannich alkali (4) is water, C with oxammonium hydrochloride condensation reaction solvent for use
1～C
6Fatty Alcohol(C12-C14 and C12-C18), methylene dichloride, chloroform, ethyl acetate, benzene, normal heptane, toluene, acetonitrile, tetrahydrofuran (THF); Used alkali is basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, trimethylamine class or quaternary ammonium bases; The molar feed ratio of alkali and oxammonium hydrochloride is 0.5～2.0: 1.0; Mannich alkali (4) is 1.0: 1.0～2.0 with the molar feed ratio of oxammonium hydrochloride; Temperature of reaction is room temperature～150 ℃; Reaction times is 0.1～48 hour.
8. pharmaceutical composition, one or more that comprise the treatment significant quantity are as each described compound of claim 1～4 or its pharmacy acceptable salt, and this pharmaceutical composition further contains one or more pharmaceutically acceptable carrier or vehicle.
9. pharmaceutical composition according to claim 8 is characterized in that, described compound or its pharmacy acceptable salt account for gross weight than 50%～99.5% as activeconstituents.
Each described compound of claim 1～4 or its pharmacy acceptable salt 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 acne or disease.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101921266A (en) * | 2010-09-02 | 2010-12-22 | 四川大学 | 3,4,6-triaryl-[1,3]-oxazine compound as well as preparation method and application thereof |
| CN101948464A (en) * | 2010-09-02 | 2011-01-19 | 四川大学 | 3,4,6-triaryl-(1,3)-oxazine-2-ketone compound as well as preparation method and application thereof |
-
2008
- 2008-04-08 CN CNA2008100445480A patent/CN101250136A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101921266A (en) * | 2010-09-02 | 2010-12-22 | 四川大学 | 3,4,6-triaryl-[1,3]-oxazine compound as well as preparation method and application thereof |
| CN101948464A (en) * | 2010-09-02 | 2011-01-19 | 四川大学 | 3,4,6-triaryl-(1,3)-oxazine-2-ketone compound as well as preparation method and application thereof |
| CN101948464B (en) * | 2010-09-02 | 2012-02-15 | 四川大学 | 3,4,6-triaryl-(1,3)-oxazine-2-ketone compound as well as preparation method and application thereof |
| CN101921266B (en) * | 2010-09-02 | 2012-07-25 | 四川大学 | 3,4,6-triaryl-[1,3]-oxazine compound as well as preparation method and application thereof |
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