CN101250134B - N-aryl-beta-aryl amidine-propionamide compounds, preparation method and use thereof - Google Patents
N-aryl-beta-aryl amidine-propionamide compounds, preparation method and use thereof Download PDFInfo
- Publication number
- CN101250134B CN101250134B CN2008100445495A CN200810044549A CN101250134B CN 101250134 B CN101250134 B CN 101250134B CN 2008100445495 A CN2008100445495 A CN 2008100445495A CN 200810044549 A CN200810044549 A CN 200810044549A CN 101250134 B CN101250134 B CN 101250134B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- propionic acid
- aryl
- acid amide
- oil
- 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
- 0 O=C(CC(c1ccc[s]1)Nc(cc1)ccc1Cl)*c(cc1)ccc1Cl Chemical compound O=C(CC(c1ccc[s]1)Nc(cc1)ccc1Cl)*c(cc1)ccc1Cl 0.000 description 2
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a non-steroidal androgen receptor modulator containing N-aryl-beta-aromatic amine-propionamide compound (I) and a relative preparation method. The invention also relates to a drug compound containing the N-aryl-beta-aromatic amine-propionamide compound (I). The N-aryl-beta-aromatic amine-propionamide compound (I) has androgen receptor antagonistic activity, therefore, thecompound 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 N-aryl-β-aryl amidine-propionamide compounds (I) and system thereof
Preparation Method, pharmaceutical composition and in the preparation prevention or/and treatment hyperplasia of prostate, prostate cancer, hirsutism,
Purposes in the medicine of symptoms such as 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 the Nonsteroic androgen acceptor regulators of N-aryl-β-aryl amidine-propionamide chemical structure (I);
Another object of the present invention is to provide the preparation method of N-aryl-β-aryl amidine-propionamide compounds (I);
Another purpose of the present invention be to provide N-aryl-β-aryl amidine-propionamide compounds (I) in the 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.
The chemical structure of N-aryl-β provided by the invention-aryl amidine-propionamide 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
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 N-aryl-β of the present invention-aryl amidine-propionamide compounds (I), when having chiral carbon in the molecule, it is raceme or optically active body.
N-aryl-β provided by the invention-available following method of aryl amidine-propionamide compounds (I) prepares: with 1,3-diaryl-3-aryl amine-1-acetone derivatives (1) is a starting raw material, in suitable solvent and alkaline condition under with the oxammonium hydrochloride condensation, get 1,3-diaryl-3-aryl amine-1-acetoxime (2); Gained intermediate 2 is reset through Beckmann under protonic acid or Lewis acid catalysis, gets N-aryl-β-aryl amidine-propionamide compounds (I), and its chemical equation is as follows:
Wherein, 1,3-diaryl-3-aryl amine-1-acetone derivatives (1) 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, pyridine; 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; 1,3-diaryl-3-aryl amine-1-acetone derivatives (1) 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.
Beckmann rearrangement reaction solvent for use is ether, tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, benzene, toluene, normal heptane, acetonitrile, and its preferred solvent is ether, tetrahydrofuran (THF); Used protonic acid is: hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, polyphosphoric acid etc., used Lewis acid is: SOCl
2, BF
3-Et
2O, PCl
5, PCl
3, POCl
3, TiCl
4, SnCl
4, AlCl
3, FeCl
3, benzene sulfonyl chloride etc., its preferred acid catalyzer is SOCl
2, BF
3-Et
2O, PCl
5Protonic acid or Lewis acid are 0.1～2.0: 1.0 with the molar feed ratio of intermediate 2, and preferred molar feed ratio is 1.0～1.5: 1.0; Temperature of reaction is-80 ℃～80 ℃, and preferable reaction temperature is-10 a ℃～room temperature; Reaction times is 1～72 hour, and the preferred reaction time is 2～24 hours.
Pharmaceutical composition provided by the invention comprises one or more N-aryl-β-aryl amidine-propionamide compounds (I) for the treatment of significant quantity, and 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 N-aryl-β-aryl amidine-propionamide compounds
(I) account for gross weight than 50%～99.5% as activeconstituents, rest part is for accounting for gross weight than below 50%.
N-aryl-β of the present invention-aryl amidine-propionamide compounds (I) has 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 1N-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-propionic acid amide
In reaction flask, add 3-phenyl-3-(4-chloroanilino)-1-(4-nitrophenyl)-1-acetone 1.9 gram (5mmol) and ethanol 20ml, 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 finishes, room temperature leaves standstill, the solid that filtration is separated out, use the ethanol/water recrystallization, get 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetoxime 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).
In dry round-bottomed flask, add 50 milliliters of 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetoxime 4.5mmol and anhydrous diethyl ethers, cryosel is bathed cooling and was stirred 15 minutes down, adds PCl in batches
5Solid 6.0mmol, 0 ℃ of left and right sides stirring reaction 15 hours (reaction process detects with TLC); After reaction finishes, add 30 milliliters of frozen water, stir after 10 minutes, use saturated NaHCO
3Aqueous solution conditioned reaction liquid pH is an alkalescence, tells ether layer, and water layer is with 10 milliliters * 2 ether extraction, combined ether layer, and anhydrous sodium sulfate drying, solvent evaporated is used ethyl alcohol recrystallization, must yellow crystals, yield 45.2%; Mp208～210 ℃.
The preparation of embodiment 2N-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-chloroanilino)-propionic acid amide
Operating process just substitutes 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone with embodiment 1 with 1-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-chloroanilino)-1-acetone, get the buff powder solid, yield 42.6%; Mp161～163 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.41 (s, 1H), 7.25 (d, 4H, J=8.8Hz), 7.09 (d, 2H, J=8.8Hz), 7.20～6.92 (m, 3H), 6.62 (d, 2H, J=8.8Hz), 5.13 (t, 1H, J=6Hz), 2.94 (d, 2H, J=6Hz), 2.30 (s, 3H); IR (KBr compressing tablet): v
NH3406.51, v
NH3356.05, v
=CH3069.80, v
C-H2918.47, v
C=O1661.17, β
NH1597.01, v
C=C1503.03, δ
CH21437.70, γ
C=C896.43-680.00; ESI-MS m/z:371 (M
++ H), 393 (M
++ Na).
The preparation of embodiment 3N-(4-aminomethyl phenyl) 3-phenyl-3-(4-chloroanilino)-propionic acid amide
Operating process just substitutes 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone with embodiment 1 with 1-(4-aminomethyl phenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone, get the white powder solid, yield 21.2%; Mp176～178 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.37～7.25 (m, 5H), 7.19 (d, 2H, J=8.0Hz), 7.08 (d, 2H, J=8.4Hz), 7.04 (d, 2H, J=9.2Hz), 6.53 (d, 2H, J=8.8Hz), 4.81 (t, 2H, J=5.2Hz), 2.86 (m, 2H), 2.29 (s, 3H); IR (KBr compressing tablet): v
NH3409.49, v
NH3247.84, v
=CH3062.83, v
C-H2922.36, v
C=O1655.34, β
NH1599.75, v
C=C1498.86, δ
CH21453.34, γ
C=C813.88-676.65; ESI-MS m/z:365 (M
++ H), 388 (M
++ Na).
The preparation of embodiment 4N-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-propionic acid amide
Operating process just substitutes 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone with embodiment 1 with 1-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetone, get the white powder solid, yield 52.9%; Mp168～170 ℃;
1H-NMR (400MHz, CDCl
3), δ: 8.04 (d, 2H, J=9.2Hz), 7.25 (d, 2H, J=8.4Hz), 7.11 (d, 2H, J=8.4Hz), 7.22～6.94 (m, 3H), 6.59 (d, 2H, J=9.2Hz), 5.27 (t, 1H, J=5.2Hz), 3.04 (dd, 1H, J
1=14.4Hz, J
2=4.8Hz), 2.89 (dd, 1H, J
1=14.2Hz, J
2=6.0Hz); IR (KBr compressing tablet): v
NH3384.22, v
=CH3108.22, v
C-H2919.85, v
C=O1660.91, β
NH1598.54, v
As NO21524.21, v
C=C1503.82, δ
CH21470.21, v
s NO21335.15, γ
C=C852.98-671.21; ESI-MS m/z:382 (M
++ H), 404 (M
++ Na).
The preparation of embodiment 5N-(4-fluorophenyl)-3-phenyl-3-(4-oil of mirbane amido)-propionic acid amide
Operating process just substitutes 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone with embodiment 1 with 1-(4-fluorophenyl)-3-phenyl-3-(4-oil of mirbane amido)-1-acetone, get the yellow powder solid, yield 30.0%; Mp146～148 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.99 (d, 2H, J=9.2Hz), 7.36～6.96 (m, 9H), 6.50 (d, 2H, J=9.2Hz), 4.95 (t, 1H, J=5.2Hz), 2.99 (dd, 1H, J
1=14Hz, J
2=4.8Hz), 2.80 (dd, 1H, J
1=14.2Hz, J
2=6.0Hz); IR (KBr compressing tablet): v
NH3354.63, v
=CH3066.80, v
C=O1665.60, β
NH1601.37, v
As NO21553.66, v
C=C1508.62, δ
CH21472.47, v
s NO21308.07, γ
C=C833.14-667.39; ESI-MS m/z:380 (M
++ H), 402 (M
++ Na).
The preparation of embodiment 6N-(4-chloro-phenyl-)-3-phenyl-3-(4-oil of mirbane amido)-propionic acid amide
Operating process just substitutes 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone with embodiment 1 with 1-(4-chloro-phenyl-)-3-phenyl-3-(4-oil of mirbane amido)-1-acetone, get the yellow powder solid, yield 25.8%; Mp180～182 ℃;
1H-NMR (400M Hz, CDCl
3) δ: 7.99 (d, 2H, J=9.2Hz), 6.49 (d, 2H, J=5.2Hz), 7.348～7.254 (m, 9H), 4.95 (t, 1H, J=5.6Hz), 2.99 (dd, 1H, J
1=14.2Hz, J
2=5.2Hz), 2.80 (dd, 1H, J
1=14.2Hz, J
2=6.0Hz); IR (KBr compressing tablet): v
NH3360.26, v
NH3316.09, v
=CH3064.63, v
C-H2924.19, v
C=O1681.04, β
NH1599.90, v
As NO21539.03, v
C=C1491.45, δ
CH21476.71, v
s NO21314.87, γ
C=C839.41-667.71; ESI-MS m/z:396 (M
++ H), 418 (M
++ Na).
The preparation of embodiment 7N-(4-chloro-phenyl-)-3-phenyl-3-(4-chloroanilino)-propionic acid amide
Operating process just substitutes 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone with embodiment 1 with 1-(4-chloro-phenyl-)-3-phenyl-3-(4-chloroanilino)-1-acetone, get the white powder solid, yield 23.7%; Mp175～177 ℃;
1H-NMR (400MHz, CDCl
3) δ: 9.26 (s, 1H), 7.45 (d, 2H, J=8.8Hz), 7.35 (d, 2H, J=7.6Hz), 7.29～7.13 (m, 7H), 7.08 (d, 2H, J=8.4Hz), 4.90 (t, 1H, J=6.8Hz), 3.97 (m, 1H), 3.53 (m, 1H); IR (KBr compressing tablet): v
NH3247.17, v
=CH3041.97, v
C=O1686.22, β
NH1596.63, v
C=C1492.64, δ
CH21458.59, γ
C=C828.36-699.43; ESI-MS m/z:385 (M
++ H), 407 (M
++ Na).
The preparation of embodiment 8N-(4-fluorophenyl)-3-phenyl-3-(4-chloroanilino)-propionic acid amide
Operating process just substitutes 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone with embodiment 1 with 1-(4-fluorophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone, get the white powder solid, yield 16.8%; Mp151～153 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.37～7.24 (m, 7H), 7.05 (d, 2H, J=9.2Hz), 6.97 (t, 2H, J=8.8Hz), 6.53 (d, 2H, J=8.8Hz), 4.82 (t, 1H, J=5.2Hz), 2.92～2.82 (m, 2H); IR (KBr compressing tablet): v
NH3410.08, v
NH3255.07, v
=CH3063.39, v
C-H2921.63, v
C=O1656.71, β
NH1600.14, v
C=C1507.81, δ
CH21454.19, γ
C=C831.20-677.45; ESI-MS m/z:369 (M
++ H).
The preparation of embodiment 9N-(4-chloro-phenyl-)-3-(2-thienyl)-3-(4-chloroanilino)-propionic acid amide
Operating process just substitutes 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone with embodiment 1 with 1-(4-chloro-phenyl-)-3-(2-thienyl)-3-(4-chloroanilino)-1-acetone, get the white powder solid, yield 12.8%; Mp146～148 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.37～6.92 (m, 7H), 7.33 (d, 2H, J=8.8Hz), 6.62 (d, 2H, J=8.8Hz), 5.13 (t, 1H, J=6Hz), 2.96 (d, 2H, J=6.0Hz); IR (KBr compressing tablet): v
NH3405.54, v
NH3247.54, v
=CH3065.92, v
C-H2913.87, v
C=O1658.89, β
NH1595.99, v
C=C1492.93, δ
CH21436.87, γ
C=C856.36-695.52; ESI-MS m/z:391 (M
++ H).
The preparation of embodiment 10N-(4-chloro-phenyl-)-3-(2-thienyl)-3-(4-oil of mirbane amido)-propionic acid amide
Operating process just substitutes 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone with embodiment 1 with 1-(4-chloro-phenyl-)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetone, get the yellow powder solid, yield 30.3%; Mp178～180 ℃;
1H-NMR (400MHz, CDCl
3) δ: 8.06 (d, 2H, J=9.2Hz), 7.33～6.95 (m, 3H), 6.61 (d, 2H, J=8.8Hz), 7.30 (d, 2H, J=9.2Hz), 7.27 (d, 2H, J=8.8Hz), 5.28 (t, 1H, J=5.2Hz), 3.06 (dd, 1H, J
1=14.4Hz, J
2=5.2Hz), 2.92 (dd, 1H, J
1=14.4Hz, J
2=5.6Hz); IR (KBr compressing tablet): v
NH3384.56, v
NH3344.57, v
=CH3108.02,, v
C=O1666.49, β
NH1596.45, v
As NO21521.76, v
C=C1503.29, δ
CH21469.70, v
s NO21334.56, γ
C=C853.21-660.08; ESI-MS m/z:402 (M
++ H).
The preparation of embodiment 11N-(4-fluorophenyl)-3-(2-thienyl)-3-(4-chloroanilino)-propionic acid amide
Operating process just substitutes 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone with embodiment 1 with 1-(4-fluorophenyl)-3-(2-thienyl)-3-(4-chloroanilino)-1-acetone, get the white powder solid, yield 26.8%; Mp156～158 ℃;
1H-NMR (400MHz, CDCl
3) δ: 7.47 (s, 1H), 7.33～6.93 (m, 7H), 7.10 (d, 2H, J=8.4Hz), 6.62 (d, 2H, J=8.8Hz), 5.14 (t, 1H, J=5.6Hz), 2.95 (d, 2H, J=5.6Hz); IR (KBr compressing tablet): v
NH3408.18, v
NH3258.87, v
=CH3068.67, v
C=O1657.65, v
C=C1597.92, β
NH1556.37, v
C=C1507.85, γ
C=C858.09-697.99; ESI-MS m/z:375 (M
++ H).
The preparation of embodiment 12N-(4-fluorophenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-propionic acid amide
Operating process just substitutes 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone with embodiment 1 with 1-(4-fluorophenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-1-acetone, get the yellow powder solid, yield 35.1%; Mp156～158 ℃;
1H-NMR (400MHz, CDCl
3) δ: 8.055 (d, 2H, J=9.2Hz), 7.33～6.96 (m, 7H), 6.61 (d, 2H, J=9.2Hz), 5.28 (t, 1H, J=5.6Hz), 3.05 (dd, 1H, J=5.2Hz), 2.91 (dd, 1H, J=5.2Hz); IR (KBr compressing tablet): v
NH3384.56, v
=CH3074.57, v
C=O1669.25, β
NH1601.34, v
As NO21526.01, v
C=C1508.53, δ
CH21470.89, v
s NO21320.10, γ
C=C835.54-670.37; ESI-MS m/z:386 (M
++ H).
The preparation of embodiment 13N-(4-fluorophenyl)-3-(2-furyl)-3-(4-oil of mirbane amido)-propionic acid amide
Operating process just substitutes 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone with embodiment 1 with 1-(4-fluorophenyl)-3-(2-furyl)-3-(4-oil of mirbane amido)-1-acetone, get the yellow powder solid, yield 28.6%; ESI-MS m/z:370 (M
++ H).
The preparation of embodiment 14N-(4-chloro-phenyl-)-3-(2-furyl)-3-(4-oil of mirbane amido)-propionic acid amide
Operating process just substitutes 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone with embodiment 1 with 1-(4-chloro-phenyl-)-3-(2-furyl)-3-(4-oil of mirbane amido)-1-acetone, get the yellow powder solid, yield 34.2%; ESI-MS m/z:386 (M
++ H).
The preparation of embodiment 15N-(4-bromophenyl)-3-(2-furyl)-3-(4-oil of mirbane amido)-propionic acid amide
Operating process just substitutes 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone with embodiment 1 with 1-(4-bromophenyl)-3-(2-furyl)-3-(4-oil of mirbane amido)-1-acetone, get the yellow powder solid, yield 32.9%; ESI-MS m/z:430 (M
++ H).
The preparation of embodiment 16N-(4-fluorophenyl)-3-(2-furyl)-3-(4-chloro-3-oil of mirbane amido)-propionic acid amide
Operating process is with embodiment 1, just 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone is substituted with 1-(4-fluorophenyl)-3-(2-furyl)-3-(4-chloro-3-oil of mirbane amido)-1-acetone, get the yellow powder solid, yield 36.5%; ESI-MS m/z:420 (M
++ H).
The preparation of embodiment 17 N-(4-chloro-phenyl-)-3-(2-furyl)-3-(4-chloro-3-oil of mirbane amido)-propionic acid amide
Operating process is with embodiment 1, just 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone is substituted with 1-(4-chloro-phenyl-)-3-(2-furyl)-3-(4-chloro-3-oil of mirbane amido)-1-acetone, get the yellow powder solid, yield 33.8%; ESI-MS m/z:436 (M
++ H).
The preparation of embodiment 18 N-(4-bromophenyl)-3-(2-furyl)-3-(4-chloro-3-oil of mirbane amido)-propionic acid amide
Operating process is with embodiment 1, just 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone is substituted with 1-(4-bromophenyl)-3-(2-furyl)-3-(4-chloro-3-oil of mirbane amido)-1-acetone, get the yellow powder solid, yield 30.1%; ESI-MS m/z:480 (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 1 N-aryl-β-aryl amidine-propionamide compounds combines activity with AR
| Compound | IC 50(nM) | ? | Compound | IC 50(nM) |
| DHT | 3.7 | ? | Amide-7 | 459.5 |
| Amide-2 | 948.5 | ? | Amide-8 | 516.2 |
| Amide-3 | 591.0 | ? | Amide-9 | 1384.0 |
| Amide-4 | 2222.0 | ? | Amide-10 | 4406.0 |
| Amide-5 | NA | ? | Amide-11 | 6967.0 |
| Amide-6 | 5691.0 | ? | Amide-12 | 2233.0 |
Above-mentioned test result shows, Amide-2, Amide-3, Amide-7, Amide-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 (8)
1. a class N-aryl-β-aryl amidine-propionamide compounds 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
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
3Or NR
5R
6R
5, R
6Expression H, C
1～C
12Alkyl or 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, furyl, thienyl or pyridyl; And this compounds is not N-phenyl-3-phenyl-3-anilino-propionic acid amide, N-(4-p-methoxy-phenyl)-3-phenyl-3-(4-anisole amido)-propionic acid amide, N-(4-chloro-phenyl-)-3-phenyl-3-anilino-propionic acid amide.
2. compound according to claim 1, it is characterized in that described compound is: N-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-propionic acid amide, N-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-chloroanilino)-propionic acid amide, N-(4-aminomethyl phenyl)-3-phenyl-3-(4-chloroanilino)-propionic acid amide, N-(4-aminomethyl phenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-propionic acid amide, N-(4-fluorophenyl)-3-phenyl-3-(4-oil of mirbane amido)-propionic acid amide, N-(4-chloro-phenyl-)-3-phenyl-3-(4-oil of mirbane amido)-propionic acid amide, N-(4-chloro-phenyl-)-3-phenyl-3-(4-chloroanilino)-propionic acid amide, N-(4-fluorophenyl)-3-phenyl-3-(4-chloroanilino)-propionic acid amide, N-(4-chloro-phenyl-)-3-(2-thienyl)-3-(4-chloroanilino)-propionic acid amide, N-(4-chloro-phenyl-)-3-(2-thienyl)-3-(4-oil of mirbane amido)-propionic acid amide, N-(4-fluorophenyl)-3-(2-thienyl)-3-(4-chloroanilino)-propionic acid amide, N-(4-fluorophenyl)-3-(2-thienyl)-3-(4-oil of mirbane amido)-propionic acid amide, N-(4-fluorophenyl)-3-(2-furyl)-3-(4-oil of mirbane amido)-propionic acid amide, N-(4-chloro-phenyl-)-3-(2-furyl)-3-(4-oil of mirbane amido)-propionic acid amide, N-(4-bromophenyl)-3-(2-furyl)-3-(4-oil of mirbane amido)-propionic acid amide, N-(4-fluorophenyl)-3-(2-furyl)-3-(4-chloro-3-oil of mirbane amido)-propionic acid amide, N-(4-chloro-phenyl-)-3-(2-furyl)-3-(4-chloro-3-oil of mirbane amido)-propionic acid amide.
3. according to the preparation method of the described compound of claim 1～2, it is characterized in that, the preparation method of described compound comprises: with 1,3-diaryl-3-aryl amine-1-acetone derivatives (1) is a starting raw material, in suitable solvent and alkaline condition under with the oxammonium hydrochloride condensation, get 1,3-diaryl-3-aryl amine-1-acetoxime (2); Gained intermediate 2 is reset through Beckmann under protonic acid or Lewis acid catalysis, gets N-aryl-β-aryl amidine-propionamide compounds (I), and its chemical equation is as follows:
4. the preparation method of N-aryl-β according to claim 3-aryl amidine-propionamide compounds (I) is characterized in that, 1, and 3-diaryl-3-aryl amine-1-acetone derivatives (1) 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 or tetrahydrofuran (THF); Used alkali is alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, 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; 1,3-diaryl-3-aryl amine-1-acetone derivatives (1) 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.
5. the preparation method of N-aryl-β according to claim 3-aryl amidine-propionamide compounds (I), it is characterized in that Beckmann rearrangement reaction solvent for use is ether, tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, benzene, toluene, normal heptane or acetonitrile; Used protonic acid is: hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid or polyphosphoric acid, used Lewis acid is: BF
3-Et
2O, PCl
5, PCl
3, POCl
3, TiCl
4, SnCl
4, AlCl
3, FeCl
3Or benzene sulfonyl chloride; Protonic acid or Lewis acid are 0.1～2.0: 1.0 with the molar feed ratio of intermediate 2; Temperature of reaction is-80 ℃～80 ℃; Reaction times is 1～72 hour.
6. pharmaceutical composition, one or more that comprise the treatment significant quantity are as each described compound of claim 1～2, and this pharmaceutical composition further contains one or more pharmaceutically acceptable carrier or vehicle.
7. pharmaceutical composition according to claim 6 is characterized in that, described compound or its pharmacy acceptable salt account for gross weight than 50%～99.5% as activeconstituents.
8. each described compound of claim 1～2 or its pharmacy acceptable salt prevent or/and the purposes in the non-steroidal drug of the symptom of treatment hyperplasia of prostate, prostate cancer, hirsutism, the dependent form alopecia of severe male sex hormone or acne or disease in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100445495A CN101250134B (en) | 2008-04-08 | 2008-04-08 | N-aryl-beta-aryl amidine-propionamide compounds, preparation method and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100445495A CN101250134B (en) | 2008-04-08 | 2008-04-08 | N-aryl-beta-aryl amidine-propionamide compounds, preparation method and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101250134A CN101250134A (en) | 2008-08-27 |
| CN101250134B true CN101250134B (en) | 2011-07-20 |
Family
ID=39953752
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008100445495A Expired - Fee Related CN101250134B (en) | 2008-04-08 | 2008-04-08 | N-aryl-beta-aryl amidine-propionamide compounds, preparation method and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101250134B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101538230B (en) * | 2008-12-30 | 2013-04-03 | 西南大学 | Beta-amino ketones compound with anti-diabetic activity |
| CN101864140B (en) * | 2010-03-05 | 2012-10-03 | 上海锦湖日丽塑料有限公司 | Dedicated styrene material for spoiler of automobile and preparation method 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 |
-
2008
- 2008-04-08 CN CN2008100445495A patent/CN101250134B/en not_active Expired - Fee Related
Non-Patent Citations (3)
| Title |
|---|
| Hata, Seiji等.Lithium Amide Assisted Asymmetric Mannich-Type Reactions of Menthyl Acetate with PMP-Aldimines.《Organic Letters》.2004,第6卷(第11期),1721-1723. * |
| Zahouily, Mohamed等.Catalysis by hydroxyapatite alone and modified by sodium nitrate: a simple and efficient procedure for the construction of carbon-nitrogen bonds in heterogeneous catalysis.《ARKIVOC》.2005,(第13期),150-161. * |
| Zankowska-Jasinska, Wanda等.Reduction of Schiff bases.《Roczniki Chemii》.1976,第50卷(第7-8期),1285-1292. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101250134A (en) | 2008-08-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101959404B (en) | AMP activated protein kinase regulator | |
| DE60036194T2 (en) | BENZIMIDAZOLE WITH VASCULARIZATION DAMAGING EFFECT | |
| CN101056862B (en) | Novel imidazolidin-2-one derivatives as selective androgen receptor modulators (SARMS) | |
| JP6928986B2 (en) | Indazole compounds, compositions and uses thereof for inhibiting kinase activity | |
| CN101400362A (en) | Bifunctional histone deacetylase inhibitors | |
| JP2011518786A (en) | Compositions and methods for preparation and use | |
| EA023104B1 (en) | Epoxyeicosatrienoic acid analogs and methods of making and using the same | |
| CN101250134B (en) | N-aryl-beta-aryl amidine-propionamide compounds, preparation method and use thereof | |
| CN1869002A (en) | Class I non-steroid androgen acceptor regulator, its preparation method and use | |
| CN102241726B (en) | Glycyrrhetinic acid derivative and application thereof as antitumor medicament | |
| CN108853109A (en) | It steps China and replaces nylon 6 combination, related compound and its preparation method and application | |
| CN1989090B (en) | Cis-1,2-substituted diphenyl ethylene derivatives and its use in preparing medine for treating and/or preventing diabetes | |
| CN103319402B (en) | Diphenyl thiourea derivatives, preparation method and applications thereof | |
| JP6985764B2 (en) | Aminopyrimidine compounds, compositions containing this compound and their use | |
| JP2010511012A (en) | Deferasirox (ICL670A) polymorphic form | |
| RU2072996C1 (en) | N-[((3,4-dichlorophenyl)-amino)-carbonyl]-2,3-dihydrobenzofu- -ran-5-sulfonamide or its pharmaceutically acceptable salt, method of its synthesis and composition showing antitumor action | |
| CN102653522B (en) | Diphenyl thiourea compounds of ω-carboxyl substituted and its production and use | |
| EA028063B1 (en) | N-[4-(quinolin-4-yloxy)cyclohexyl(methyl)](hetero)arylcarboxamides as androgen receptor antagonists, production and use thereof as medicinal products | |
| CN101597280B (en) | Compound used as seven-pass transmembrane protein and based on sag structure | |
| CN102532099A (en) | Composition, synthesis and application of hydantoin derivatives | |
| CN101250136A (en) | 1,3-diaryl-3-aryl amidine-1-acetoxime compounds, preparation method and use thereof | |
| EP1742947B1 (en) | 6-substituted pyridoindolone derivatives production and therapeutic use thereof | |
| CN109516938A (en) | A kind of Alfacalcidol derivative and preparation method thereof | |
| CN111039880B (en) | Application of miconazole and derivative thereof as TGR5 agonist | |
| CN100551364C (en) | The purposes of 3-(3-nitro-4-hydroxyl) phenyl-ethyl acrylate in the medicine of preparation inhibition xanthine oxidase |
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 | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110720 Termination date: 20140408 |