CN101857595A - Quinnazolidone derivative, preparation method thereof and purpose of serving as anticarcinogen - Google Patents
Quinnazolidone derivative, preparation method thereof and purpose of serving as anticarcinogen Download PDFInfo
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Abstract
The invention belongs to the medicine and chemical industry field, which discloses a quinnazolidone derivative, a preparation method thereof and a purpose of serving as anticarcinogen. The structural formula of the quinnazolidone derivative is that: R1 is F, CL, Br or I, R2 is NH (CH2) nNR4, NR4 or NH(CH2)n-Ar, R3 is NHCO (CH2) nNR4 or CONH (CH2) nNR4, and m equals to 1,2 or 3. -Ar represents various aromatic nucleus, including various heteroaromatic compounds; n equals to 1, 2, 3, 4 or 5; R4 represents C1-6alkyl, C3-6 naphthenic base, piperidyl, morpholinyl, piperazine, or quinoxaline and the like or R1 equals to H, R2 equals to R3 equals to NHCO (CH2) nNR4 or R2 equals to H, R1 equals to R3 equals to NHCO (CH2) nNR4, and m equals to 2 or 3. The invention discloses the preparation method of the quinnazolidone derivative and the purpose of serving as the anticarcinogen at the same time. The quinnazolidone derivative has the advantages of strong inhibitory action on the expression of telomere DNA, c-myc and other proto-oncogenes DNA, obvious inhibitory action on various cancer cell strains, little toxicity on normal cells and wide application space on preparing the anticarcinogen.
Description
Technical field
The invention belongs to medicine and chemical field, relate to a kind of Quinzolone derivatives and preparation method thereof, with and be used for the purposes of cancer therapy drug in preparation.
Background technology
Cancer is the principal disease that threatens human health and life security, and according to statistics, the whole world annual newly-increased cancer patients reach about 4,000,000 people.The research and development of cancer therapy drug are the focuses that chemist and medicine scholar pay close attention to always.Seek efficient, highly selective, cancer therapy drug that toxic side effect is little is one of important directions of drug development research.Synthesizing cancer therapy drug for target spot designs with DNA, at the special higher structure design synthesized micromolecule inhibitor of proto-oncogene DNA such as telomeric dna with important physiological significance and c-myc, is the important method of development new type anticancer medicine particularly.
The quinazolone Alkaloid is the big class of one in the alkaloid, is the primary structure unit of traditional Chinese medicine ingredients febrifugin(e).These compositions mainly are present in the Chinese medicines such as Changshan, Leaf of Indigowoad, NSC 290495, couroupitine A etc. have wide biological activity.Studies show that in recent years, the compound that contains this class formation has the multi-biological activity, brings into play multiple pharmacological effect such as anticancer, antibiotic, antiviral.Patent application 200810027004 disclose a kind of pair of fat amido replace Quinzolone derivatives with and as the application of cancer therapy drug, still, the development research of quinazolone class biology is still considerably less at present.
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, the Quinzolone derivatives that a kind of toxicity is little, anticancer effect is good is provided.
Another object of the present invention is to provide the preparation method of this Quinzolone derivatives.
A further object of the invention is to provide the application of this Quinzolone derivatives.
Invention is achieved through the following technical solutions above-mentioned purpose:
Invention provides a kind of Quinzolone derivatives, and its structural formula is:
Wherein each group can be one of following arbitrary combination:
Combination one:
R
1Be F, Cl, Br or I;
R
2Be NH (CH
2)
nNR
4, NR
4Or NH (CH
2)
n-Ar;
R
3Be NHCO (CH
2)
nNR
4
M=1,2 or 3.
Wherein ,-Ar can be various aromatic nucleus, comprises various aromatic heterocycles; N=1,2,3,4 or 5; R
4Group can be C
1-6Alkyl, C
3-6Cycloalkyl, piperidyl, morpholinyl, piperazinyl Huo Bi Evil quinoline base etc.
Combination two:
Except R
3Be CONH (CH
2)
nNR
4Outside, other as the combination one;
Combination three:
R
1=H, R
2=R
3=NHCO (CH
2)
nNR
4; Perhaps R
2=H, R
1=R
3=NHCO (CH
2)
nNR
4
M=2 or 3.
Wherein, n=1,2,3,4 or 5, R
4Group can be C
1-6Alkyl, C
3-6Cycloalkyl, piperidyl, morpholinyl, piperazinyl Huo Bi Evil quinoline base etc.
The present invention provides the preparation method of this Quinzolone derivatives simultaneously, is expressed as follows:
(1) works as R
1=F, Cl, Br or I, m=1, R
2Be NH (CH
2)
nNR
4, NR
4Or NH (CH
2)
n-Ar, R
3=NHCO (CH
2)
nNR
4The time, building-up process is:
The steps include: that 2-benzaminic acid and pyrrolidone that 4,5 two halogens replace close ring, obtain compound F 17-hydroxy-corticosterone-I1, F-I1 and different substituted amine compound (NH (CH
2) nNR
4, NR
4Or NH (CH
2) n-Ar) substitution reaction takes place, obtain compound F 17-hydroxy-corticosterone-I2, the phenyl aldehyde condensation that F-I2 replaces with nitro again obtains chemical combination
Thing F-I3 is then through Na
2The S reduction obtains compound F 17-hydroxy-corticosterone-I4.Alkyl acyl chloride [Cl (the CH that F-I4 and chlorine replace
2)
nCOCl] carry out after alkylated reaction obtains the alkylation intermediate, again with substituted amine compound (NHR
4) effect, obtain target product (the described Quinzolone derivatives of claim 1) by column chromatography or recrystallization.
(2) work as R
1=F, Cl, Br or I, m=2 or 3, R
2Be NH (CH
2)
nNR
4, NR
4Or NH (CH
2)
n-Ar, R
3=NHCO (CH
2)
nNR
4The time, building-up process is:
The steps include: that 2-benzaminic acid and various lactan that 4,5 two halogens replace close ring, obtain compound F 17-hydroxy-corticosterone-H1, F-H1 elder generation and the phenyl aldehyde condensation that nitro replaces obtain compound F 17-hydroxy-corticosterone-H2, then through Na
2S reduction obtains compound F 17-hydroxy-corticosterone-H3, F-H3 again with different substituted amine compound (NH (CH
2)
nNR
4, NR
4Or NH (CH
2)
n-Ar) substitution reaction takes place, obtain compound F 17-hydroxy-corticosterone-H4, the alkyl acyl chloride [Cl (CH that F-H4 and chlorine replace
2)
nCOCl] carry out after alkylated reaction obtains the alkylation intermediate, again with substituted amine compound (NHR
4) effect, obtain target product (the described Quinzolone derivatives of claim 1) by column chromatography or recrystallization.
(3) work as R
1=F, Cl, Br or I, m=1, R
2Be NH (CH
2)
nNR
4, NR
4Or NH (CH
2)
n-Ar, R
3=CONH (CH
2)
nNR
4The time, building-up process is:
The steps include: by described process before, obtain F-I2 after, with the condensation of 4-carbamoyl benzoate, obtain compound F 17-hydroxy-corticosterone-C3, F-C3 again with different substituted amine compound (NH (CH
2)
nNR
4) reaction, obtain target product (the described Quinzolone derivatives of claim 2) by column chromatography or recrystallization.
(4) work as R
1=F, Cl, Br or I, m=2 or 3, R
2Be NH (CH
2)
nNR
4, NR
4Or NH (CH
2)
n-Ar, R
3=CONH (CH
2)
nNR
4The time, building-up process is:
The steps include: by described process before, obtain F-H1 after, with the condensation of 4-carbamoyl benzoate, obtain compound F 17-hydroxy-corticosterone-D2, F-D2 and different substituted amine compound (NH (CH earlier
2)
nNR
4, NHR
4Or NH (CH
2)
n-Ar) substitution reaction takes place, obtain compound F 17-hydroxy-corticosterone-D3, F-D3 again with different substituted amine compound (NH (CH
2)
nNR
4) reaction, obtain target product (the described Quinzolone derivatives of claim 2) by column chromatography or recrystallization.
(5) as m=2 or 3, R
1=H, R
2=R
3=NHCO (CH
2)
nNR
4; Perhaps R
2=H, R
1=R
3=NHCO (CH
2)
nNR
4The time, building-up process is:
The steps include: 4 or 5 2-benzaminic acid and various lactan pass rings that nitro replaces, obtain compound 2.The 2 phenyl aldehyde condensations that replace with nitro obtain compound 3, then through Na
2The S reduction obtains compound 4.4 alkyl acyl chloride [Cl (the CH that replace with chlorine
2)
nCOCl] carry out after alkylated reaction obtains intermediate, again with substituted amine compound (NHR
4) effect and recrystallization obtain target product (the described Quinzolone derivatives of claim 3).
The present invention is open simultaneously and protected this Quinzolone derivatives in the purposes for preparing on the cancer therapy drug; And the cancer therapy drug that contains this Quinzolone derivatives.
Compared with prior art, the present invention has following beneficial effect:
(1) experimental results show that, novel quinazoline ketone derivatives disclosed in this invention has very strong interaction with proto-oncogene DNA such as telomeric dna that is rich in guanine and c-myc, demonstration has the good restraining activity to the telomere/Telomerase in the cancer cells, expression to proto-oncogene c-myc has very strong restraining effect, show significant antitumous effect, can be used for preparation and have the selectivity cancer therapy drug.
(2) further experiment proves, the novel quinazoline ketone derivatives that the present invention relates to has significant inhibitory effect to multiple JEG-3, and little to normal cytotoxicity, on the preparation cancer therapy drug wide application space is arranged.
Embodiment
Below further specify technical scheme of the present invention by specific embodiment.
Embodiment one: compound 2b's is synthetic
0.01mol exsiccant 4-nitro-2-benzaminic acid and 0.005mol Valerolactim are dissolved in the 250m1 toluene, drip the phosphorus oxychloride of 3ml under the room temperature, refluxed 8 hours.Reaction solution is slowly poured in the frozen water, regulates pH to weakly alkaline, and suction filtration gets yellow solid.Filtrate is with (removal of solvent under reduced pressure merges gained solid before for 3 * 100mL) ethyl acetate extractions, collected organic layer, and crude product gets light yellow solid powder 2b through column chromatography purification (cyclohexane/ethyl acetate).
Productive rate: 37%; 1H NMR (400MHz, CDCl3) δ 8.44 (d, J=2.1Hz, 1H), 8.41 (d, J=8.8Hz, 1H), 8.17 (dd, J=8.8,2.1Hz, 1H), 4.10 (t, J=6.2Hz, 2H), 3.05 (t, J=6.6Hz, 2H), 2.10-1.95 (m, 4H); ESI-MS m/z:246[M+H]
+.
Compound 2b
Embodiment two: compound 2e's is synthetic
Method is with embodiment one, and different is with 5-nitro-2-aminobenzoic acid substitution 4-nitro-2-benzaminic acid, gets faint yellow solid 2e.
Productive rate: 50%; 1H NMR (400MHz, CDCl3) δ 9.13 (d, J=2.6Hz, 1H), 8.50 (dd, J=9.0,2.6Hz, 1H), 7.71 (d, J=9.0Hz, 1H), 4.11 (t, J=6.2Hz, 2H), 3.06 (t, J=6.6Hz, 2H), 2.09-1.96 (m, 4H); ESI-MS m/z:246[M+H]
+.
Compound 2e
Embodiment three: compound 2c's is synthetic
Method is with embodiment one, and different is to replace Valerolactim with hexanolactam, gets faint yellow solid 2c.
Productive rate: 25%; 1H NMR (400MHz, CDCl3) δ 8.41 (d, J=2.1Hz, 1H), 8.38 (d, J=8.8Hz, 1H), 8.16 (dd, J=8.8,2.1Hz, 1H), 4.46-4.36 (m, 2H), 3.17-3.07 (m, 2H), 1.97-1.80 (m, 6H); ESI-MS m/z:260[M+H]
+.
Compound 2c
Embodiment four: compound 2f's is synthetic
Method is with embodiment one, and different is with 5-nitro-2-aminobenzoic acid substitution 4-nitro-2-benzaminic acid, and replaces Valerolactim with hexanolactam, gets faint yellow solid 2f.
Productive rate: 45%; 1H NMR (400MHz, CDCl3) δ 9.07 (d, J=2.6Hz, 1H), 8.47 (dd, J=9.0,2.6Hz, 1H), 7.68 (d, J=9.0Hz, 1H), 4.48-4.36 (m, 2H), 3.18-3.06 (m, 2H), 1.96-1.81 (m, 6H); ESI-MS m/z:260[M+H]
+.
Compound 2f
Embodiment five: compound 3b's is synthetic
With 0.005mol compound 2b and 0.01mol 4-nitrobenzaldehyde, and 0.001mol NaOAc is dissolved in the 10ml acetate back flow reaction 8 hours, reaction is chilled to room temperature after finishing, suction filtration gets solid, and with chloroform (100ml) and acetone (200ml) washing, gets light yellow solid 3b.
Productive rate: 93%; 1H NMR (400MHz, DMSO) δ 8.45 (d, J=2.1Hz, 1H), 8.41-8.26 (m, 4H), 8.22 (dd, J=8.8,2.1Hz, 1H), 7.85 (d, J=8.7Hz, 2H), 4.15-4.04 (m, 2H), 3.00-2.88 (m, 2H), 2.07-1.94 (m, 2H); ESI-MS m/z:379[M+H]
+.
Compound 3b
Embodiment six: compound 3e's is synthetic
Method is with embodiment five, and different is to replace compound 2b with compound 2e, gets faint yellow solid 3e.
Productive rate: 93%; 1H NMR (400MHz, DMSO) δ 8.84 (d, J=2.4Hz, 1H), 8.56 (dd, J=9.0,2.4Hz, 1H), 8.37 (s, 1H), 8.31 (d, J=8.7Hz, 2H), 7.90 (d, J=9.0Hz, 1H), 7.85 (d, J=8.7Hz, 2H), 4.13-4.05 (m, 2H), 2.98-2.91 (m, 2H), 2.04-1.96 (m, 2H); ESI-MS m/z:379[M+H]
+.
Compound 3e
Embodiment seven: compound 3c's is synthetic
Method is with embodiment five, and different is to replace compound 2b with compound 2c, gets faint yellow solid 3c.
Productive rate: 42%; 1H NMR (400MHz, CDCl3) δ 8.60 (d, J=2.1Hz, 1H), 8.47 (d, J=8.7Hz, 1H), 8.30 (d, J=8.7Hz, 2H), 8.26 (dd, J=8.7,2.1Hz, 1H), 7.67 (d, J=8.7Hz, 2H), 7.23 (s, 1H), 4.38-4.30 (m, 2H), 2.87-2.79 (m, 2H), 2.03-1.90 (m, 4H); ESI-MS m/z:393[M+H]
+.
Compound 3c
Embodiment eight: compound 3f's is synthetic
Method is with embodiment five, and different is to replace compound 2b with compound 2f, gets faint yellow solid 3f.
Productive rate: 40%; 1H NMR (400MHz, CDCl3) δ 9.16 (d, J=2.6Hz, 1H), 8.55 (dd, J=8.9,2.6Hz, 1H), 8.30 (d, J=8.7Hz, 2H), 7.86 (d, J=8.9Hz, 1H), 7.67 (d, J=8.7Hz, 2H), 7.25 (s, 1H), 4.38-4.32 (m, 2H), 2.88-2.81 (m, 2H), 2.04-1.90 (m, 4H); ESI-MS m/z:393[M+H]
+.
Compound 3f
Embodiment nine: compound 4b's is synthetic
3b is dissolved in 50ml ethanol with the 0.005mol compound, and past adding is dissolved with the 80ml aqueous solution of 0.02mol nine water cure sodium and 0.05mol sodium hydroxide, refluxes 6 hours, and ethanol is removed in decompression, is cooled to 0-5 ℃, and suction filtration obtains the thick product of garnet after the washing repeatedly.Thick product ethanol/acetone recrystallization gets orange red solid 4b.
Productive rate: 91%; 1H NMR (400MHz, DMSO) δ 7.91 (s, 1H), 7.73 (d, J=8.6Hz, 1H), 7.27 (d, J=8.5Hz, 2H), 6.65 (dd, J=8.6,2.1Hz, 1H), 6.61 (d, J=8.5Hz, 2H), 6.60-6.57 (m, 1H), 5.96 (s, 2H), 5.57 (s, 2H), 4.00-3.90 (m, 2H), 2.87-2.78 (m, 2H), 1.93-1.83 (m, 2H); ESI-MS m/z:319[M+H]
+.
Compound 4b
Embodiment ten: compound 4e's is synthetic
Method is with embodiment nine, and different is to replace compound 3b with compound 3e, gets faint yellow solid 4e.
Productive rate: 90%; 1H NMR (400MHz, DMSO) δ 7.83 (d, J=2.0Hz, 1H), 7.38 (d, J=8.7Hz, 1H), 7.24 (d, J=8.5Hz, 2H), 7.18 (s, 1H), 7.07 (dd, J=8.7,2.0Hz, 1H), 6.61 (d, J=8.5Hz, 2H), 5.55 (s, 2H), 5.51 (s, 2H), 4.05-3.95 (m, 2H), 2.87-2.79 (m, 2H), 1.94-1.84 (m, 2H); ESI-MS m/z:319[M+H]
+.
Compound 4e
Embodiment 11: compound 4c's is synthetic
Method is with embodiment nine, and different is to replace compound 3b with compound 3c, gets faint yellow solid 4c.
Productive rate: 60%; 1H NMR (400MHz, DMSO) δ 7.76 (d, J=8.6Hz, 1H), 7.25 (d, J=8.6Hz, 2H), 6.79 (s, 1H), 6.70 (dd, J=8.6,2.2Hz, 1H), 6.64-6.59 (m, 3H), 6.03 (s, 2H), 5.44 (s, 2H), 4.09-4.03 (m, 2H), 2.70-2.64 (m, 2H), 1.80-1.67 (m, 4H); ESI-MS m/z:333[M+H]
+.
Compound 4c
Embodiment 12: Compound P-a1's is synthetic
0.0005mol compound 4b is suspended in the 2-chloroacetyl chloride of 10ml, back flow reaction 4 hours is after reaction is finished, cooling is put 0-5 ℃, suction filtration, and solid washs 2 times with ether, get the alkylation intermediate, this intermediate and 50mg KI are suspended in the 5ml ethanol again, past Dropwise 5 ml is dissolved with the ethanol of 0.005mol Pyrrolidine, back flow reaction 3 hours adds 20ml water, is cooled to 0 ℃, suction filtration, with the ether washing, crude product chloroform/ethanol recrystallization obtains light yellow solid powder P-a1.
Productive rate: 60%; 1H NMR (400MHz, CDCl
3) δ (ppm): 9.45 (s, 1H), 9.25 (s, 1H), 8.18-8.26 (m, 2H), 7.96 (d, J=1.8Hz, 1H), 7.62-7.71 (m, 3H), 7.48 (d, J=8.5Hz, 2H), 4.19-4.11 (m, 2H), 3.33 (d, J=9.2Hz, 4H), 2.90-3.00 (m, 2H), 2.63-2.80 (m, 8H), 1.98-2.08 (m, 2H), 1.82-1.94 (m, 8H); ESI-MS m/z:541[M+H]
+.
Compound P-a1
Embodiment 13: Compound P-a2's is synthetic
Method is with embodiment 13, and different is to replace Pyrrolidine with piperidines, gets faint yellow solid P-a2.Productive rate: 62%; 1H NMR (400MHz, CDCl
3) δ=9.64 (s, 1H), 9.43 (s, 1H), 8.26-8.18 (m, 2H), 7.93 (d, J=2.0Hz, 1H), 7.71-7.62 (m, 3H), 7.48 (d, J=8.6Hz, 2H), 4.20-4.11 (m, 2H), 3.12 (d, J=7.9Hz, 4H), 2.96 (t, J=5.5Hz, 2H), 2.68-2.48 (m, 8H), 2.09-1.99 (m, 2H), and 1.71-1.65 (m, 8H), 1.56-1.46 (m, 4H); ESI-MS m/z:569[M+H]
+.
Compound P-a2
Embodiment 14: Compound P-a3's is synthetic
Method is with embodiment 13, and different is to replace Pyrrolidine with diethylamine, gets faint yellow solid P-a3.
Productive rate: 58%; 1H NMR (400MHz, CDCl
3) δ=9.74 (s, 1H), 9.54 (s, 1H), 8.26-8.18 (m, 2H), 7.93 (s, 1H), 7.71-7.63 (m, 3H), 7.48 (d, J=8.2,2H), 4.18-4.11 (m, 2H), 3.21 (s, 4H), 2.96 (t, J=6.1,2H), and 2.77-2.60 (m, 8H), 2.07-1.99 (m, 2H), 1.12 (t, J=6.9,12H); ESI-MS m/z:545[M+H]
+.
Compound P-a3
Embodiment 15: Compound P-b1's is synthetic
Method is with embodiment 13, and different is to replace the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, gets faint yellow solid P-b1.
Productive rate: 73%; 1H NMR (400MHz, CDCl3) δ=11.68 (s, 1H), 11.45 (s, 1H), 8.23-8.13 (m, 2H), 7.83 (d, J=1.8,1H), 7.62-7.51 (m, 3H), 7.45 (d, J=8.5,2H), 4.18-4.10 (m, 2H), 2.95 (t, J=5.6,2H), 2.92-2.84 (m, 4H), 2.78-2.65 (m, 8H), 2.61-2.53 (m, 4H), and 2.06-2.00 (m, 2H), 1.98-1.88 (m, 8H); ESI-MS m/z:569[M+H]
+.
Compound P-a1
Embodiment 16: Compound P-b2's is synthetic
Method is with embodiment 13, and different is to replace the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, and replaces Pyrrolidine with piperidines, gets faint yellow solid P-b2.
Productive rate: 76%; 1H NMR (400MHz, CDCl
3) δ=11.77 (s, 1H), 11.60 (s, 1H), 8.23-8.14 (m, 2H), and 7.97-7.90 (m, 1H), 7.66-7.55 (m, J=8.5Hz, 3H), 7.47 (d, J=8.5Hz, 2H), 4.18-4.11 (m, 2H), 2.96 (t, J=5.7Hz, 2H), 2.80-2.46 (m, 16H), 2.07-2.01 (m, 2H), 1.81-1.70 (m, 8H), 1.67-1.50 (m, 4H); ESI-MS m/z:597[M+H]
+.
Compound P-b2
Embodiment 17: Compound P-b3's is synthetic
Method is with embodiment 13, and different is to replace the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, and replaces Pyrrolidine with diethylamine, gets faint yellow solid P-b3.
Productive rate: 70%; 1H NMR (400MHz, CDCl
3) δ=11.69 (s, 1H), 11.45 (s, 1H), 8.19 (d, J=8.7,1H), 8.16 (s, 1H), 7.85 (d, J=1.8,1H), 7.63 (dd, J=8.7,1.8,1H), 7.60 (d, J=8.6,1H), 7.45 (d, J=8.6,1H), 4.18-4.10 (m, 2H), 2.95 (t, J=5.5,2H), 2.86-2.78 (m, 4H), 2.78-2.66 (m, 4H), 2.61-2.51 (m, 4H), 2.05-1.98 (m, 2H), 1.24-1.10 (m, 12H); ESI-MS m/z:573[M+H]
+.
Compound P-b3
Embodiment 18: compound M-a1's is synthetic
Method is with embodiment 13, and different is to replace 4b with 4e, gets faint yellow solid M-a1.
Productive rate: 52%; 1H NMR (400MHz, CDCl
3) δ=9.46 (s, 1H), 9.26 (s, 1H), 8.41 (dd, J=8.9,2.3,1H), 8.15 (s, 1H), 8.07 (d, J=2.3,1H), 7.72 (d, J=8.9,1H), 7.66 (d, J=8.5,2H), 7.47 (d, J=8.5,2H), 4.23-4.12 (m, 2H), 3.38-3.27 (m, 4H), 2.97 (t, J=5.6,2H), 2.81-2.67 (m, 8H), and 2.11-1.98 (m, 2H), 1.94-1.86 (m, 8H); ESI-MSm/z:541[M+H]
+.
Compound M-a1
Embodiment 19: compound M-a2's is synthetic
Method is with embodiment 13, and different is to replace 4b with 4e, and replaces Pyrrolidine with piperidines, gets faint yellow solid M-a2.
Productive rate: 53%; 1H NMR (400MHz, CDCl
3) δ=9.61 (s, 1H), 9.46 (s, 1H), 8.39 (dd, J=8.9,2.3,1H), 8.16 (s, 1H), 8.09 (s, J=2.3,1H), 7.72 (d, J=8.9,1H), 7.66 (d, J=8.5,2H), 7.48 (d, J=8.5,2H), 4.21-4.14 (m, 2H), 3.23-3.07 (m, 4H), 2.97 (t, J=5.6,2H), 2.69-2.52 (m, 8H), 2.08-2.00 (m, 2H), 1.77-1.64 (m, 8H), 1.57-1.48 (m, 4H); ESI-MS m/z:569[M+H]
+.
Compound M-a2
Embodiment 20: compound M-a3's is synthetic
Method is with embodiment 13, and different is to replace 4b with 4e, and replaces Pyrrolidine with diethylamine, gets faint yellow solid M-a3.
Productive rate: 50%; 1H NMR (400MHz, CDCl
3) δ=9.72 (s, 1H), 9.54 (s, 1H), 8.41 (dd, J=8.9,2.3,1H), 8.16 (s, 1H), 8.06 (s, J=2.3,1H), 7.73 (d, J=8.9,1H), 7.66 (d, J=8.6,2H), 7.48 (d, J=8.6,2H), 4.20-4.13 (m, 2H), 3.25-3.12 (m, J=4.5,4H), 3.00-2.93 (m, 2H), 2.74-2.61 (m, 8H), and 2.08-1.99 (m, 2H), 1.15-1.08 (m, 12H); ESI-MS m/z:545[M+H]
+.
Compound M-a3
Embodiment 21: compound M-b1's is synthetic
Method is with embodiment 13, and different is to replace 4b with 4e, and replaces the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, gets faint yellow solid M-b1.
Productive rate: 65%; 1H NMR (400MHz, CDCl3) δ=11.56 (s, 1H), 11.45 (s, 1H), 8.24 (dd, J=8.8Hz, 1.9Hz, 1H), 8.13 (s, 1H), 8.01 (d, J=1.9Hz, 1H), 7.69 (d, J=8.8Hz, 1H), 7.55 (d, J=8.4Hz, 2H), 7.44 (d, J=8.4Hz, 2H), 4.22-4.09 (m, 2H), 3.01-2.93 (m, 2H), 2.93-2.83 (m, 4H), 2.78-2.65 (m, 8H), 2.63-2.52 (m, 4H), 2.06-1.99 (m, 2H), 1.96-1.89 (m, 8H); ESI-MS m/z:569[M+H]
+.
Compound M-b1
Embodiment 22: compound M-b2's is synthetic
Method is with embodiment 13, and different is to replace 4b with 4e, replaces the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, and replaces Pyrrolidine with piperidines, gets faint yellow solid M-b2.
Productive rate: 67%; 1H NMR (400MHz, CDCl
3) δ=11.71 (s, 1H), 11.55 (s, 1H), 8.28 (dd, J=8.9,2.1,1H), 8.13 (s, 1H), 8.09 (s, J=2.1,1H), 7.70 (d, J=8.9,1H), 7.61 (d, J=8.4,2H), 7.45 (d, J=8.4,2H), 4.22-4.10 (m, 2H), 2.96 (t, J=6.0,2H), 2.78-2.43 (m, 16H), 2.07-1.99 (m, 2H), and 1.80-1.70 (m, 8H), 1.64-1.53 (m, 4H); ESI-MS m/z:597[M+H]
+.
Compound M-b2
Embodiment 23: compound M-b3's is synthetic
Method is with embodiment 13, and different is to replace 4b with 4e, replaces the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, and replaces Pyrrolidine with diethylamine, gets faint yellow solid M-b3.
Productive rate: 64%; 1H NMR (400MHz, CDCl
3) δ=11.61 (s, 1H), 11.47 (s, 1H), 8.29 (dd, J=8.9,2.3,1H), 8.13 (s, 1H), 8.04 (d, J=2.3,1H), 7.69 (d, J=8.9,1H), 7.59 (d, J=8.5,2H), 7.44 (d, J=8.5,2H), 4.19-4.11 (m, 2H), 2.95 (t, J=5.8,2H), 2.84-2.76 (m, 4H), 2.76-2.65 (m, 8H), 2.59-2.49 (m, 4H), 2.07-1.98 (m, 2H), 1.22-1.11 (m, 12H); ESI-MS m/z:573[M+H]
+.
Compound M-b3
Embodiment 24: Compound P-h1's is synthetic
Method is with embodiment 13, and different is to replace 4b with 4c, replaces the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, gets yellow solid P-h1.
Productive rate: 57%; 1H NMR (400MHz, CDCl
3) δ 11.61 (s, 1H), 11.32 (s, 1H), 8.14 (d, J=8.7Hz, 1H), 7.70 (d, J=8.7Hz, 1H), 7.66 (s, 1H), 7.47 (d, J=8.4Hz, 2H), 7.38 (d, J=8.4Hz, 2H), 6.98 (s, 1H), 4.27-4.16 (m, 2H), 2.85-2.77 (m, 4H), 2.76-2.70 (m, 2H), 2.68-2.59 (m, 8H), and 2.53-2.47 (m, 4H), 1.89-1.77 (m, 12H); ESI-MS m/z:583[M+H]
+.
Compound P-h1
Embodiment 25: Compound P-h2's is synthetic
Method is with embodiment 13, and different is to replace 4b with 4c, replaces the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, and replaces Pyrrolidine with piperidines, gets yellow solid P-h2.
Productive rate: 56%; 1H NMR (400MHz, CDCl
3) δ 11.72 (s, 1H), 11.53 (s, 1H), 8.23 (d, J=8.7Hz, 1H), 7.84 (s, 1H), 7.77 (s, J=8.7Hz, 1H), 7.60 (d, J=8.3Hz, 2H), 7.47 (d, J=8.3Hz, 2H), 7.07 (s, 1H), 4.33-4.24 (m, 2H), 2.86-2.79 (m, 2H), 2.72-2.66 (m, 4H), 2.65-2.48 (m, 12H), 1.95-1.85 (m, 4H), and 1.77-1.70 (m, 8H), 1.62-1.53 (m, 4H); ESI-MS m/z:611[M+H]
+.
Compound P-h2
Embodiment 26: compound F 17-hydroxy-corticosterone-I1's is synthetic
With 5.19g exsiccant 4,5-difluoro anthranilic acid (30mmol) is dissolved in the 500ml exsiccant toluene with 7.65g pyrrolidone (90mmol), drips the phosphorus oxychloride of 15ml under the room temperature, refluxes 8 hours.After the cooling, reaction solution is slowly poured in an amount of frozen water, is alkalescence with the ammoniacal liquor regulator solution, and suction filtration is collected solid, behind the solid drying, uses the acetone heating for dissolving, and suction filtration discards insoluble solids, and concentrating under reduced pressure acetone waits the thick product of part.Toluene layer is collected in the filtrate extraction, and vacuum rotary steam behind the anhydrous magnesium sulfate drying also obtains the thick product of part.After the thick product of two portions merges, pass through the silica gel column chromatography purifying as eluent, obtain light grey to white solid F-I1 with petrol ether/ethyl acetate (volume ratio 4/1).
Productive rate be 56%:1H NMR (400MHz, CDCl3) δ 8.02 (dd, J=10.0,8.6Hz, 1H), 7.42 (dd, J=10.8,7.0Hz, 1H), 4.21 (t, J=8.0Hz, 2H), 3.18 (t, J=8.0Hz, 2H), 2.35-2.27 (m, 2H); LC-MS m/z:223[M+H]
+.
Compound F 17-hydroxy-corticosterone-I1
Embodiment 27: compound F 17-hydroxy-corticosterone-I2's is synthetic
1.11g exsiccant F-I1 (5mmol) is dissolved among the DMF of 18ml with the N methyl piperazine (22.5mmol) of 2.5ml, the yellow soda ash that adds catalytic amount, 140 ℃ were reacted 2 hours, the decompression rotary evaporation is removed part DMF, then solution is poured in the 30ml water into suction filtration, get white solid, wash with water repeatedly, drying gets white solid.
Productive rate 87%:1H NMR (400MHz, CDCl3) δ 7.82 (d, J=13.0Hz, 1H), 7.08 (d, J=7.8Hz, 1H), 4.18 (t, J=8.0Hz, 2H), 3.30 (t, J=4.0Hz, 4H), 3.14 (t, J=8.0Hz, 2H), 2.64 (t, J=4.0Hz, 4H), 2.38 (s, 3H), and 2.31-2.24 (m, 2H); LC-MS m/z:303[M+H]
+.
Compound F 17-hydroxy-corticosterone-I2
Embodiment 28: compound F 17-hydroxy-corticosterone-I3's is synthetic
With 3.02g exsiccant F-I2 (10mmol) and 3.02g paranitrobenzaldehyde (20mmol) mixed dissolution in 70ml acetate, the sodium acetate that adds catalytic amount, 115 ℃ of back flow reaction 6 hours, part acetate is removed in decompression, adds 15ml acetone, is cooled to 0-5 ℃, suction filtration, behind twice of the solid usefulness 15ml washing with acetone, drying gets yellow powder shape solid.
Productive rate 78%:1H NMR (400MHz, CDCl3) δ 8.31 (d, J=8.8Hz, 2H), 7.88 (d, J=13.0Hz, 1H), 7.84 (s, 1H), 7.70 (d, J=8.8Hz, 2H), 7.19 (d, J=7.8Hz, 1H), 4.32 (t, J=8.0Hz, 2H), and 3.37-3.33 (m, 6H), 2.69 (t, J=4.0Hz, 4H), 2.41 (s, 3H); LC-MSm/z:436[M+H]
+.
Compound F 17-hydroxy-corticosterone-I3
Embodiment 29: compound F 17-hydroxy-corticosterone-I4's is synthetic
1.74g F-I3 (4mmol) is dissolved in 40ml ethanol, toward wherein adding the 60ml aqueous solution that is dissolved with 2.88g nine water cure sodium (12mmol) and 2.4g sodium hydroxide (60mmol), 90 ℃ were refluxed 6 hours, the decompression rotary evaporation is removed most of second alcohol and water, be chilled to room temperature, suction filtration obtains the red-brown product after the washing repeatedly.Thick product passes through purification by silica gel column chromatography with methyl alcohol/chloroform (volume ratio 1/50 to 1/10) as eluent, obtains orange/yellow solid.
Productive rate 84%:1H NMR (400MHz, CDCl3) δ 7.83 (d, J=13.0Hz, 1H), 7.69 (s, 1H), 7.40 (d, J=8.4Hz, 2H), 7.15 (d, J=7.8Hz, 1H), 6.72 (d, J=8.5Hz, 2H), 4.25 (t, J=8.0Hz, 2H), 3.95 (s, 2H), 3.31 (t, J=4.0Hz, 4H), 3.25 (t, J=6.2Hz, 2H), 2.64 (t, J=4.0Hz, 4H), 2.39 (s, 3H); LC-MS m/z:406[M+H]
+.
Compound F 17-hydroxy-corticosterone-I4
Embodiment 30: compound F 17-hydroxy-corticosterone-H1's is synthetic
Method is with embodiment 27, and the raw material that closes ring has changed Valerolactim into by pyrrolidone, obtains grey to white solid F-H1.
Productive rate 58%:1H NMR (400MHz, DMSO) δ 7.98 (dd, J=9.9,9.4Hz, 1H), 7.63 (dd, J=11.5,7.3Hz, 1H), 3.93 (t, J=6.2Hz, 2H), 2.90 (t, J=6.6Hz, 2H), 1.99-1.88 (m, 2H), 1.87-1.74 (m, 2H); LC-MS m/z:237[M+H]
+.
Compound F 17-hydroxy-corticosterone-H1
Embodiment hentriaconta-: compound F 17-hydroxy-corticosterone-H2's is synthetic
Method is with embodiment 29, and different is to replace F-I2 with F-H1, gets yellow solid.
Productive rate 83%:1H NMR (400MHz, DMSO) δ 8.30 (d, J=8.7Hz, 2H), 8.21 (s, 1H), 8.09-8.02 (m, 1H), 7.86-7.75 (m, 3H), 4.06 (t, J=6.0Hz, 2H), 2.92 (t, J=5.4Hz, 2H), 2.01-1.94 (m, 2H); LC-MS m/z:370[M+H]
+.
Compound F 17-hydroxy-corticosterone-H2
Embodiment 32: compound F 17-hydroxy-corticosterone-H3's is synthetic
Method is with embodiment 30, and different is to replace F-I3 with F-H2, and solvent replaces ethanol with acetonitrile, gets yellow solid.
Productive rate 91%:1H NMR (400MHz, CDCl3) δ 8.12 (s, 1H), 8.00 (dd, J=10.0,8.7Hz, 1H), 7.54-7.44 (m, 1H), 7.37 (d, J=8.5Hz, 2H), 6.72 (d, J=8.6Hz, 2H), 4.16-4.11 (m, 2H), 3.97 (br, 2H), 2.99-2.92 (m, 2H), and 2.08-1.98 (m, 2H); LC-MS m/z:340[M+H]
+..
Compound F 17-hydroxy-corticosterone-H3
Embodiment 33: compound F 17-hydroxy-corticosterone-H4's is synthetic
Method is with embodiment 28, and different is to replace F-I1 with F-H3, and replaces DMF to make solvent with DMSO, gets yellow solid.
Productive rate 87%:1H NMR (400MHz, CDCl3) δ 8.04 (s, 1H), 7.81 (d, J=13.0Hz, 1H), 7.34 (d, J=8.5Hz, 2H), 7.13 (d, J=7.9Hz, 1H), 6.71 (d, J=8.5Hz, 2H), 4.12 (t, J=6.0Hz, 2H), 3.88 (s, 2H), 3.33 (br, 4H), 2.94 (t, J=5.6Hz, 2H), 2.68 (br, 4H), 2.41 (s, 3H), 2.05-1.97 (m, 2H); LC-MS m/z:420[M+H]
+.
Compound F 17-hydroxy-corticosterone-H4
Embodiment 34: compound F 17-hydroxy-corticosterone P-a1's is synthetic
0.81g F-I4 (2mmol) is suspended in the 2-chloroacetyl chloride of 7ml, back flow reaction 4 hours, system is cooled to 0-5 ℃, suction filtration, solid respectively washs 3 times with 15ml chloroform and 15ml ether, obtain the 0.91g yellow solid, get this intermediate of 0.5mmol and catalytic amount sodium iodide and join in the dehydrated alcohol of 5ml, be heated to backflow, toward Pyrrolidine and the 2ml alcoholic acid mixing solutions of system Dropwise 5 mmol, back flow reaction 4 hours, add a small amount of ether, be cooled to 0 ℃, suction filtration, with the ether washing repeatedly, get thick product.Thick product is by purification by silica gel column chromatography, eluent be chloroform/methanol=500/1 to 50/1, can get light yellow solid after the purifying.
Productive rate 30%:1H NMR (400MHz, CDCl3) δ 9.29 (s, 1H), 7.85 (d, J=13.0Hz, 1H), 7.76 (s, 1H), 7.69 (d, J=8.5Hz, 2H), 7.54 (d, J=8.6Hz, 2H), 7.17 (d, J=7.8Hz, 1H), 4.28 (t, J=7.2Hz, 2H), 3.41-3.23 (m, 8H), 2.80-2.62 (m, 8H), 2.41 (s, 3H), 1.89 (s, 4H); LC-MS m/z:517[M+H]
+.
Compound F 17-hydroxy-corticosterone P-a1
Embodiment 35: compound F 17-hydroxy-corticosterone P-a2's is synthetic
Method is with embodiment 35, and different is to replace Pyrrolidine with diethylamine, gets light yellow solid.
Productive rate 33%:1H NMR (400MHz, CDCl3) δ 9.59 (s, 1H), 7.86 (d, J=12.9Hz, 1H), 7.76 (s, 1H), 7.69 (d, J=8.4Hz, 2H), 7.55 (d, J=8.4Hz, 2H), 7.18 (d, J=7.8Hz, 1H), 4.28 (t, J=7.1Hz, 2H), 3.38 (s, 4H), 3.30 (t, J=6.0Hz, 2H), 3.19 (s, 2H), 2.84-2.61 (m, 8H), 2.46 (s, 3H), 1.11 (t, J=7.1Hz, 6H); LC-MS m/z:519[M+H]
+.
Compound F 17-hydroxy-corticosterone P-a2
Embodiment 36: compound F 17-hydroxy-corticosterone P-a3's is synthetic
Method is with embodiment 35, and different is to replace Pyrrolidine with piperidines, gets light yellow solid.
Productive rate 52%:1H NMR (400MHz, CDCl3) δ 9.45 (s, 1H), 7.85 (d, J=12.9Hz, 1H), 7.76 (s, 1H), 7.68 (d, J=8.6Hz, 2H), 7.55 (d, J=8.7Hz, 2H), 7.17 (d, J=7.8Hz, 1H), 4.28 (t, J=8.0Hz, 2H), 3.39-3.25 (m, 6H), 3.11 (s, 2H), 2.68 (s, 4H), 2.57 (t, J=4.0Hz, 4H), 2.41 (s, 3H), and 1.70-1.64 (m, 4H), 1.51-1.46 (m, 2H); LC-MS m/z:531[M+H]
+.
Compound F 17-hydroxy-corticosterone P-a3
Embodiment 37: compound F 17-hydroxy-corticosterone P-a4's is synthetic
Method is with embodiment 35, and different is to replace F-I4 with F-H4, gets light yellow solid.
Productive rate 29%:1H NMR (400MHz, CDCl3) δ 9.24 (s, 1H), 8.12 (s, 1H), 7.82 (d, J=13.0Hz, 1H), 7.66 (d, J=8.6Hz, 2H), 7.47 (d, J=8.6Hz, 2H), 7.15 (d, J=7.8Hz, 1H), 4.14 (t, J=6.0Hz, 2H), 3.36-3.26 (m, 6H), 2.96 (t, J=5.5Hz, 2H), 2.72 (t, J=5.2Hz, 4H), 2.66 (t, J=4.0Hz, 4H), 2.40 (s, 3H), 2.05-2.00 (m, 2H), 1.91-1.87 (m, 4H); LC-MS m/z:531[M+H]
+.
Compound F 17-hydroxy-corticosterone P-a4
Embodiment 38: compound F 17-hydroxy-corticosterone P-a5's is synthetic
Method is with embodiment 35, and different is to replace F-I4 with F-H4, and replaces Pyrrolidine with diethylamine, gets light yellow solid.
Productive rate 30%:1H NMR (400MHz, CDCl3) δ 9.53 (s, 1H), 8.11 (s, 1H), 7.82 (d, J=12.9Hz, 1H), 7.65 (d, J=8.6Hz, 2H), 7.47 (d, J=8.5Hz, 2H), 7.15 (d, J=7.9Hz, 1H), 4.13 (t, J=6.0Hz, 2H), 3.32 (t, J=4.0Hz, 4H), 3.17 (s, 2H), 2.95 (t, J=5.6Hz, 2H), 2.70-2.62 (m, 3H), 2.39 (s, 3H), 2.05-1.98 (m, 2H), 1.11 (t, J=7.1Hz, 6H); LC-MS m/z:533[M+H]
+.
Compound F 17-hydroxy-corticosterone P-a5
Embodiment 39: compound F 17-hydroxy-corticosterone P-a6's is synthetic
Method is with embodiment 35, and different is to replace F-I4 with F-H4, and replaces Pyrrolidine with piperidines, gets light yellow solid.
Productive rate 41%:1H NMR (400MHz, CDCl3) δ 9.40 (s, 1H), 8.11 (s, 1H), 7.81 (d, J=12.9Hz, 1H), 7.64 (d, J=8.5Hz, 2H), 7.47 (d, J=8.5Hz, 2H), 7.14 (d, J=7.8Hz, 1H), 4.13 (t, J=6.0Hz, 2H), 3.31 (t, J=4.0Hz, 4H), 3.10 (s, 2H), 2.94 (t, J=6.0Hz, 2H), 2.65 (br, 4H), 2.56 (br, 4H), 2.39 (s, 3H), 2.04-2.00 (m, 2H), 1.70-1.63 (m, 4H), 1.54-1.48 (m, 2H); LC-MS m/z:545[M+H]
+.
Compound F 17-hydroxy-corticosterone P-a6
Embodiment 40: compound F 17-hydroxy-corticosterone P-b1's is synthetic
Method is with embodiment 35, and different is to replace the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, gets light yellow solid.
Productive rate 18%:1H NMR (400MHz, CDCl3) δ 11.43 (s, 1H), 7.76 (d, J=13.0Hz, 1H), 7.66 (br, 1H), 7.51 (d, J=8.6Hz, 2H), 7.43 (d, J=8.6Hz, 2H), 7.08 (d, J=7.8Hz, 1H), 4.19 (t, J=7.2Hz, 2H), 3.27-3.17 (m, 6H), 2.81 (t, J=6.0Hz, 2H), 2.64 (br, 4H), 2.56 (br, J=4.3Hz, 4H), 2.50 (t, J=6.0Hz, 2H), 2.30 (s, 3H), 1.85 (br, 4H); LC-MS m/z:531[M+H]
+.
Compound F 17-hydroxy-corticosterone P-b1
Embodiment 41: compound F 17-hydroxy-corticosterone P-b2's is synthetic
Method is with embodiment 35, and different is to replace the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, and replaces Pyrrolidine with diethylamine, gets light yellow solid.
Productive rate 34%:1H NMR (400MHz, CDCl3) δ 11.56 (s, 1H), 7.81 (d, J=12.9Hz, 1H), 7.72 (s, 1H), 7.62 (d, J=8.6Hz, 2H), 7.50 (d, J=8.6Hz, 2H), 7.14 (d, J=7.8Hz, 1H), 4.25 (t, J=7.2Hz, 2H), 3.31 (t, J=6.0Hz, 4H), 3.26 (t, J=8.0Hz, 2H), 2.80 (t, J=6.0Hz, 2H), 2.70 (q, J=7.1Hz, 4H), 2.63 (t, J=4.0Hz, 4H), 2.53 (t, J=6.0Hz, 2H), 2.37 (s, 3H), 1.16 (t, J=7.1Hz, 6H); LC-MS m/z:533[M+H]
+.
Compound F 17-hydroxy-corticosterone P-b2
Embodiment 42: compound F 17-hydroxy-corticosterone P-b3's is synthetic
Method is with embodiment 35, and different is to replace the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, and replaces Pyrrolidine with piperidines, gets light yellow solid.
Productive rate 25%:1H NMR (400MHz, CDCl3) δ 11.62 (s, 1H), 7.83 (d, J=12.9Hz, 1H), 7.73 (s, 1H), 7.64 (d, J=8.1Hz, 2H), 7.51 (d, J=8.0Hz, 2H), 7.16 (d, J=7.5Hz, 1H), 4.26 (t, J=8.0Hz, 2H), 3.38-3.22 (m, 6H), 2.74-2.51 (m, 12H), 2.38 (s, 3H), 1.73 (br, 4H), 1.59 (br, 2H); LC-MS m/z:545[M+H]
+.
Compound F 17-hydroxy-corticosterone P-b3
Embodiment 43: compound F 17-hydroxy-corticosterone P-b4's is synthetic
Method is with embodiment 35, and different is to replace the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, and replaces F-I4 with F-H4, gets light yellow solid.
Productive rate 31%:1H NMR (400MHz, CDCl3) δ 11.25 (s, 1H), 8.09 (s, 1H), 7.81 (d, J=13.0Hz, 1H), 7.57 (d, J=8.6Hz, 2H), 7.44 (d, J=8.5Hz, 2H), 7.14 (d, J=7.9Hz, 1H), 4.13 (t, J=6.0Hz, 2H), 3.31 (t, J=6.0Hz, 4H), 2.94 (t, J=5.7Hz, 4H), 2.77 (br, 4H), 2.67-2.59 (m, 6H), 2.38 (s, 3H), 2.04-1.99 (m, 2H), 1.94 (br, 4H); LC-MS m/z:545[M+H]
+.
Compound F 17-hydroxy-corticosterone P-b4
Embodiment 44: compound F 17-hydroxy-corticosterone P-b5's is synthetic
Method is with embodiment 35, and different is to replace the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, and replaces F-I4 with F-H4, and replaces Pyrrolidine with diethylamine, gets light yellow solid.
Productive rate 30%:1H NMR (400MHz, CDCl3) δ 11.42 (s, 1H), 8.09 (s, 1H), 7.81 (d, J=13.0Hz, 1H), 7.61 (d, J=8.5Hz, 2H), 7.44 (d, J=8.5Hz, 2H), 7.14 (d, J=7.8Hz, 1H), 4.13 (t, J=6.0Hz, 2H), 3.31 (t, 4H), 2.94 (t, J=5.7Hz, 2H), 2.83 (t, J=6.0Hz, 2H), 2.72 (q, J=14.3,7.1Hz, 4H), 2.64 (t, J=4.0Hz, 4H), 2.56 (t, J=4.0Hz, 2H), 2.38 (s, 3H), 2.03-1.98 (m, 2H), 1.17 (t, J=7.1Hz, 6H); LC-MS m/z:547[M+H]
+.
Compound F 17-hydroxy-corticosterone P-b5
Embodiment 45: compound F 17-hydroxy-corticosterone P-b6's is synthetic
Method is with embodiment 35, and different is to replace the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, and replaces F-I4 with F-H4, and replaces Pyrrolidine with piperidines, gets light yellow solid.
Productive rate 32%:1H NMR (400MHz, CDCl3) δ 11.48 (s, 1H), 8.09 (s, 1H), 7.81 (d, J=13.0Hz, 1H), 7.62 (d, J=8.5Hz, 2H), 7.44 (d, J=8.5Hz, 2H), 7.15 (d, J=7.9Hz, 1H), 4.13 (t, J=6.0Hz, 2H), 3.31 (t, J=4.0Hz, 4H), 2.95 (t, J=5.6Hz, 2H), 2.72 (t, J=6.0Hz, 2H), and 2.68-2.50 (m, 10H), 2.38 (s, 3H), and 2.05-1.99 (m, 2H), 1.78-1.70 (m, 4H), 1.58 (br, 2H); LC-MS m/z:559[M+H]
+.
Compound F 17-hydroxy-corticosterone P-b6
Embodiment 46: compound F 17-hydroxy-corticosterone-C3's is synthetic
Method is with embodiment 29, and different is to use carboxyl benzaldehyde is replaced paranitrobenzaldehyde, obtains light yellow solid.
Productive rate 73%:1H NMR (400MHz, DMSO) δ 10.11 (s, 1H), 8.02 (d, J=8.6Hz, 2H), 7.79-7.73 (m, 3H), 7.71 (d, J=13.2Hz, 1H), 7.19 (d, J=8.1Hz, 1H), 4.17 (t, J=6.9Hz, 2H), 3.23 (br, 6H), 2.54 (br, 4H), 2.27 (s, 3H); LC-MS m/z:435[M+H]
+.
Compound F 17-hydroxy-corticosterone-C3
Embodiment 47: compound F 17-hydroxy-corticosterone-D2's is synthetic
Method is with embodiment 29, and different is to use carboxyl benzaldehyde is replaced paranitrobenzaldehyde, and replaces F-I2 with F-H1, obtains light yellow solid.
Productive rate 75%:1H NMR (400MHz, DMSO) δ 10.11 (s, 0H), 8.18 (s, 1H), and 8.05-8.00 (m, 3H), 7.76 (dd, J=11.4,7.3Hz, 1H), 7.65 (d, J=8.3Hz, 2H), 4.05 (t, J=6.0Hz, 2H), 2.92 (t, J=6.0Hz, 2H), and 2.01-1.93 (m, 2H); LC-MS m/z:369[M+H]
+.
Compound F 17-hydroxy-corticosterone-D2
Embodiment 48: compound F 17-hydroxy-corticosterone-D3's is synthetic
Method is with embodiment 28, and different is to replace F-I1 with F-D2, and replaces DMF with DMSO, obtains light yellow solid.
Productive rate 71%:1H NMR (400MHz, DMSO) δ 8.17 (s, 1H), 7.99 (d, J=8.3Hz, 2H), 7.67 (d, J=13.1Hz, 1H), 7.62 (d, J=8.3Hz, 2H), 7.15 (d, J=8.1Hz, 1H), 4.03 (t, J=6.0Hz, 2H), 3.21 (t, J=4.4Hz, 4H), 2.91 (t, J=6.0Hz, 2H), 2.54-2.51 (m, 4H), 2.25 (s, 3H), 1.98-1.92 (m, 2H); LC-MS m/z:449[M+H]
+.
Compound F 17-hydroxy-corticosterone-D3
Embodiment 49: compound F 17-hydroxy-corticosterone P-C1's is synthetic
0.217g F-C3 (0.5mmol) is dissolved among the 4mlDMF, add 0.14ml triethylamine (1mmmol), toward the 2-Pyrrolidine base ethamine (1mmol) that wherein drips 0.16ml, 0.33gBOP (0.75mmol) and the solution of 4mlDMF, 60 ℃ were reacted 3 hours, and most of DMF, water and dichloromethane extraction are removed in decompression, concentrate organic phase, get thick product.Thick product is by purification by silica gel column chromatography, eluent be chloroform/methanol=500/1 to 50/1, can get light yellow solid after the purifying.
Productive rate 41%:1H NMR (400MHz, CDCl3) δ 7.75 (d, J=8.1Hz, 2H), 7.64-7.57 (m, 2H), 7.40 (d, J=8.1Hz, 2H), 7.23 (t, J=4.4Hz, 1H), 6.99 (d, J=7.7Hz, 1H), 4.09 (t, J=6.9Hz, 2H), 3.53-3.47 (m, 2H), 3.24-3.18 (m, 4H), 3.12-3.05 (m, 2H), 2.67 (t, J=5.8Hz, 2H), 2.57-2.50 (m, 8H), 2.29 (s, 3H), 1.77-1.71 (m, 4H); LC-MS m/z:531[M+H]
+.
Compound F 17-hydroxy-corticosterone P-C1
Embodiment 50: compound F 17-hydroxy-corticosterone P-C2's is synthetic
Method is with embodiment 50, and different is to replace 2-Pyrrolidine base ethamine with 2-diethylin ethamine, obtains light yellow solid.
Productive rate 44%:
1H NMR (400MHz, CDCl
3) δ 7.74 (d, J=8.3Hz, 2H), 7.63-7.58 (m, 2H), 7.42 (d, J=8.3Hz, 2H), 7.19 (t, J=4.8Hz, 1H), 6.99 (d, J=7.8Hz, 1H), 4.10 (t, J=7.1Hz, 2H), 3.46-3.40 (m, 2H), 3.23-3.18 (m, 4H), 3.09 (t, J=5.8Hz, 2H), 2.60 (t, J=6.0Hz, 2H), 2.55-2.48 (m, 8H), 2.28 (s, 3H), 0.98 (t, J=7.1Hz, 6H); LC-MSm/z:533[M+H]
+.
Compound F 17-hydroxy-corticosterone P-C2
Embodiment 51: compound F 17-hydroxy-corticosterone P-C3's is synthetic
Method is with embodiment 50, and different is to replace 2-Pyrrolidine base ethamine with the 2-dimethylaminoethylam,ne, obtains light yellow solid.
Productive rate 35%:
1H NMR (400MHz, CDCl
3) δ 7.66 (d, J=8.2Hz, 2H), 7.51-7.44 (m, 2H), 7.29 (d, J=8.3Hz, 2H), 7.16 (t, J=4.9Hz, 1H), 6.88 (d, J=7.8Hz, 1H), 3.97 (t, J=7.1Hz, 2H), 3.44-3.38 (m, 2H), 3.17-3.09 (m, 4H), 2.95 (t, J=5.7Hz, 2H), 2.50-2.41 (m, J=13.9,7.8Hz, 6H), 2.23 (s, 3H), 2.17 (s, 6H); LC-MSm/z:505[M+H]
+.
Compound F 17-hydroxy-corticosterone P-C3
Embodiment 52: compound F 17-hydroxy-corticosterone P-C4's is synthetic
Method is with embodiment 50, and different is to replace 2-Pyrrolidine base ethamine with 2-piperidyl ethamine, obtains light yellow solid.
Productive rate 39%:
1H NMR (400MHz, CDCl
3) δ 7.80 (d, J=8.1Hz, 2H), 7.70-7.64 (m, J=13.0Hz, 2H), 7.47 (d, J=8.2Hz, 2H), 7.40 (t, J=4.3Hz, 1H), 7.05 (d, J=7.8Hz, 1H), 4.15 (t, J=7.0Hz, 2H), 3.54-3.49 (m, 2H), 3.27-3.22 (m, 4H), 3.17-3.14 (m, J=5.4Hz, 2H), and 2.59-2.52 (m, 6H), 2.46-2.38 (m, 4H), 2.32 (s, 3H), and 1.61-1.55 (m, 4H), 1.47-1.40 (m, 2H); LC-MSm/z:545[M+H]
+.
Compound F 17-hydroxy-corticosterone P-C4
Embodiment 53: compound F 17-hydroxy-corticosterone P-C5's is synthetic
Method is with embodiment 50, and different is to replace F-C3 with F-D3, obtains light yellow solid.
Productive rate 30%:
1H NMR (400MHz, CDCl
3) δ 8.07 (s, 1H), 7.78 (d, J=8.2Hz, 2H), 7.70 (d, J=12.9Hz, 1H), 7.42 (d, J=8.2Hz, 2H), 7.11 (t, J=4.5Hz, 1H), 7.03 (d, J=7.8Hz, 1H), 4.02 (t, J=6.0Hz, 2H), 3.53-3.47 (m, 2H), 3.24-3.17 (m, 4H), 2.83 (t, J=5.3Hz, 2H), 2.65 (t, J=5.9Hz, 2H), 2.56-2.52 (m, 4H), 2.52-2.47 (m, 4H), 2.28 (s, 3H), 1.95-1.89 (m, 2H), 1.75-1.69 (m, 4H); LC-MSm/z:545[M+H]
+.
Compound F 17-hydroxy-corticosterone P-C5
Embodiment 54: compound F 17-hydroxy-corticosterone P-C6's is synthetic
Method is with embodiment 50, and different is to replace F-C3 with F-D3, and replaces 2-Pyrrolidine base ethamine with 2-diethylin ethamine, obtains light yellow solid.
Productive rate 28%:
1H NMR (400MHz, CDCl
3) δ 8.08 (s, 1H), 7.78 (d, J=8.2Hz, 2H), 7.70 (d, J=12.9Hz, 1H), 7.43 (d, J=8.2Hz, 2H), 7.21 (t, J=4.5Hz, 1H), 7.04 (d, J=7.8Hz, 1H), 4.03 (t, J=4.0Hz, 2H), 3.47-3.42 (m, 2H), 3.24-3.18 (m, 4H), 2.84 (t, J=5.4Hz, 2H), 2.61 (t, J=5.9Hz, 2H), 2.56-2.49 (m, 8H), 2.29 (s, 3H), 1.96-1.89 (m, 2H), 0.99 (t, J=7.1Hz, 6H); LC-MSm/z:547[M+H]
+.
Compound F 17-hydroxy-corticosterone P-C6
Embodiment 55: compound F 17-hydroxy-corticosterone P-C7's is synthetic
Method is with embodiment 50, and different is to replace F-C3 with F-D3, and replaces 2-Pyrrolidine base ethamine with the 2-dimethylaminoethylam,ne, obtains light yellow solid.
Productive rate 33%:
1H NMR (400MHz, CDCl
3) δ 8.09 (s, 1H), 7.81 (d, J=8.2Hz, 2H), 7.72 (d, J=12.9Hz, 1H), 7.44 (d, J=8.2Hz, 2H), 7.11 (t, J=4.7Hz, 1H), 7.06 (d, J=7.8Hz, 1H), 4.05 (t, J=6.0Hz, 2H), 3.52-3.48 (m, 2H), 3.26-3.20 (m, 4H), 2.85 (t, J=5.5Hz, 2H), 2.59-2.54 (m, 4H), 2.50 (t, J=5.8Hz, 2H), 2.30 (s, 3H), 2.24 (s, 6H), 1.98-1.91 (m, 2H); LC-MSm/z:519[M+H]
+.
Compound F 17-hydroxy-corticosterone P-C7
Embodiment 56: compound F 17-hydroxy-corticosterone P-C8's is synthetic
Method is with embodiment 50, and different is to replace F-C3 with F-D3, and replaces 2-Pyrrolidine base ethamine with 2-piperidyl ethamine, obtains light yellow solid.
Productive rate 27%:
1H NMR (400MHz, CDCl
3) δ 8.07 (s, 1H), 7.77 (d, J=8.2Hz, 2H), 7.69 (d, J=12.9Hz, 1H), 7.42 (d, J=8.2Hz, 2H), 7.18 (t, J=4.6Hz, 1H), 7.02 (d, J=7.8Hz, 1H), 4.02 (t, J=6.0Hz, 2H), 3.49-3.43 (m, 2H), 3.24-3.17 (m, 4H), 2.83 (t, J=5.5Hz, 2H), and 2.56-2.50 (m, 4H), 2.48 (t, J=6.0Hz, 2H), 2.42-2.31 (m, 4H), 2.28 (s, 3H), 1.95-1.88 (m, 2H), 1.55-1.48 (m, 4H), 1.42-1.34 (m, 2H); LC-MS m/z:559[M+H]
+.
Compound F 17-hydroxy-corticosterone P-C8
Embodiment 57: compound F 17-hydroxy-corticosterone P-D1's is synthetic
Method is with embodiment 50, and different is to replace 2-Pyrrolidine base ethamine with 3-Pyrrolidine base propylamine, obtains light yellow solid.
Productive rate 39%:
1H NMR (400MHz, CDCl
3) δ 8.81 (t, J=4.3Hz, 1H), 7.72 (d, J=8.2Hz, 2H), 7.65-7.60 (m, 2H), 7.42 (d, J=8.3Hz, 2H), 7.00 (d, J=7.8Hz, 1H), 4.12 (t, J=7.1Hz, 2H), 3.53-3.47 (m, 2H), and 3.25-3.18 (m, 4H), 3.11 (t, J=6.0Hz, 2H), 2.63 (t, J=6.0Hz, 2H), 2.56-2.48 (m, 8H), 2.29 (s, 3H), 1.78-1.70 (m, 6H); LC-MS m/z:545[M+H]
+.
Compound F 17-hydroxy-corticosterone P-D1
Embodiment 58: compound F 17-hydroxy-corticosterone P-D2's is synthetic
Method is with embodiment 50, and different is to replace 2-Pyrrolidine base ethamine with the 3-diethyl amino propylamine, obtains light yellow solid.
Productive rate 40%:
1H NMR (400MHz, CDCl
3) δ 8.74 (t, J=4.4Hz, 1H), 7.73 (d, J=8.3Hz, 2H), 7.65-7.57 (m, 2H), 7.42 (d, J=8.3Hz, 2H), 6.98 (d, J=7.8Hz, 1H), 4.10 (t, J=7.1Hz, 2H), 3.54-3.44 (m, 2H), 3.19 (t, J=6.0Hz, 4H), 3.11 (t, J=6.0Hz, 2H), 2.59-2.45 (m, 10H), 2.27 (s, 3H), 1.74-1.64 (m, 2H), 0.96 (t, J=7.1Hz, 6H); LC-MS m/z:547[M+H]
+.
Compound F 17-hydroxy-corticosterone P-D2
Embodiment 59: compound F 17-hydroxy-corticosterone P-D3's is synthetic
Method is with embodiment 50, and different is to replace 2-Pyrrolidine base ethamine with the 3-dimethylaminopropylamine, obtains light yellow solid.
Productive rate 28%:
1H NMR (400MHz, CDCl
3) δ 8.44 (s, 1H), 7.67 (d, J=8.0Hz, 2H), 7.53-7.45 (m, 2H), 7.33 (d, J=8.0Hz, 2H), 6.91 (d, J=7.7Hz, 1H), 4.02 (t, J=6.0Hz, 2H), 3.47-3.38 (m, 2H), 3.19-3.09 (m, 4H), 3.03-2.95 (m, 2H), 2.52-2.45 (m, 4H), 2.43 (t, J=6.2Hz, 2H), 2.24 (s, 3H), 2.23 (s, 6H), 1.74-1.66 (m, 2H); LC-MS m/z:519[M+H]
+.
Compound F 17-hydroxy-corticosterone P-D3
Embodiment 60: compound F 17-hydroxy-corticosterone P-D4's is synthetic
Method is with embodiment 50, and different is to replace 2-Pyrrolidine base ethamine with 3-piperidyl propylamine, obtains light yellow solid.
Productive rate 31%:
1H NMR (400MHz, CDCl
3) δ 8.58 (s, 1H), 7.73 (d, J=8.0Hz, 2H), 7.58-7.52 (m, 2H), 7.37 (d, J=8.0Hz, 2H), 6.94 (d, J=7.7Hz, 1H), 4.06 (t, J=6.8Hz, 2H), 3.45-3.41 (m, 2H), 3.20-3.13 (m, 4H), and 3.08-3.00 (m, 2H), 2.52-2.46 (m, 4H), 2.43-2.39 (m, 2H), 2.38-2.27 (m, 4H), 2.25 (s, 3H), 1.69 (t, J=6.0Hz, 2H), 1.51-1.45 (m, 4H), 1.41-1.33 (m, 2H); LC-MS m/z:559[M+H]
+.
Compound F 17-hydroxy-corticosterone P-D4
Embodiment 61: compound F 17-hydroxy-corticosterone P-D5's is synthetic
Method is with embodiment 50, and different is to replace F-C3 with F-D3, and replaces 2-Pyrrolidine base ethamine with 3-Pyrrolidine base propylamine, and with obtaining light yellow solid.
Productive rate 30%:
1H NMR (400MHz, CDCl
3) δ 8.88 (s, 1H), 8.07 (s, 1H), 7.74 (d, J=8.1Hz, 2H), 7.68 (d, J=12.9Hz, 1H), 7.40 (d, J=8.1Hz, 2H), 7.02 (d, J=7.8Hz, 1H), 4.02 (t, J=4.0Hz, 2H), and 3.52-3.47 (m, 2H), 3.23-3.16 (m, 4H), 2.86-2.81 (m, 2H), 2.63 (t, J=6.0Hz, 2H), 2.55-2.47 (m, 8H), 2.27 (s, 3H), 1.95-1.89 (m, 2H), 1.76-1.70 (m, 6H); LC-MS m/z:559[M+H]
+.
Compound F 17-hydroxy-corticosterone P-D5
Embodiment 62: compound F 17-hydroxy-corticosterone P-D6's is synthetic
Method is with embodiment 50, and different is to replace F-C3 with F-D3, and replaces 2-Pyrrolidine base ethamine with the 3-diethyl amino propylamine, obtains light yellow solid.
Productive rate 25%:
1H NMR (400MHz, CDCl
3) δ 8.85 (s, 1H), 8.11 (s, 1H), 7.79 (d, J=8.1Hz, 2H), 7.74 (d, J=12.9Hz, 1H), 7.45 (d, J=8.1Hz, 2H), 7.07 (d, J=7.8Hz, 1H), 4.07 (t, J=4.0Hz, 2H), 3.56-3.51 (m, 2H), 3.27-3.21 (m, 4H), 2.88 (t, J=5.4Hz, 2H), 2.60-2.51 (m, 10H), 2.32 (s, 3H), 2.00-1.93 (m, 2H), 1.76-1.68 (m, 2H), 1.00 (t, J=7.1Hz, 6H); LC-MS m/z:561[M+H]
+.
Compound F 17-hydroxy-corticosterone P-D6
Embodiment 63: compound F 17-hydroxy-corticosterone P-D7's is synthetic
Method is with embodiment 50, and different is to replace F-C3 with F-D3, and replaces 2-Pyrrolidine base ethamine with the 3-dimethylaminopropylamine, obtains light yellow solid.
Productive rate 27%:
1H NMR (400MHz, CDCl
3) δ 8.55 (t, J=4.3Hz, 1H), 8.10 (s, 1H), 7.76 (d, J=8.2Hz, 2H), 7.72 (d, J=12.9Hz, 1H), 7.44 (d, J=8.2Hz, 2H), 7.05 (d, J=7.8Hz, 1H), 4.05 (t, J=6.0Hz, 2H), 3.54-3.48 (m, 2H), 3.26-3.20 (m, 4H), 2.87 (t, J=5.5Hz, 2H), 2.59-2.53 (m, 4H), 2.45 (t, J=5.9Hz, 2H), 2.30 (s, 3H), 2.25 (s, 6H), 1.98-1.91 (m, 2H), 1.76-1.69 (m, 2H); LC-MSm/z:533[M+H]
+.
Compound F 17-hydroxy-corticosterone P-D7
Embodiment 64: compound F 17-hydroxy-corticosterone P-D8's is synthetic
Method is with embodiment 50, and different is to replace F-C3 with F-D3, and replaces 2-Pyrrolidine base ethamine with 3-piperidyl propylamine, obtains light yellow solid.
Productive rate 27%:
1H NMR (400MHz, CDCl
3) δ 8.71 (t, J=4.4Hz, 1H), 8.13 (s, 1H), 7.86 (d, J=8.3Hz, 2H), 7.76 (d, J=12.9Hz, 1H), 7.47 (d, J=8.2Hz, 2H), 7.09 (d, J=7.9Hz, 1H), 4.09 (t, J=6.0Hz, 2H), 3.56-3.51 (m, 2H), 3.28-3.22 (m, 4H), 2.89 (t, J=5.5Hz, 2H), 2.60-2.56 (m, 4H), 2.54 (t, J=6.0Hz, 2H), 2.52-2.35 (m, 4H), 2.33 (s, 3H), 2.01-1.95 (m, 2H), 1.82-1.75 (m, 2H), 1.62-1.55 (m, 4H), 1.50-1.40 (m, 2H); LC-MS m/z:573[M+H]
+.
Compound F 17-hydroxy-corticosterone P-D8
Embodiment 65: compound F 17-hydroxy-corticosterone-E2's is synthetic
Method is with embodiment 28, and different is to replace N methyl piperazine with piperidines, obtains white solid.
Productive rate 82%:
1H NMR (400MHz, CDCl3) δ 7.80 (d, J=13.0Hz, 1H), 7.06 (d, J=7.9Hz, 1H), 4.18 (t, J=6.0Hz, 2H), 3.20 (t, J=4.0Hz, 4H), 3.14 (t, J=7.9Hz, 2H), 2.31-2.23 (m, 2H), 1.79-1.72 (m, 4H), and 1.66-1.62 (m, 2H); LC-MS m/z:288[M+H]
+.
Compound F 17-hydroxy-corticosterone-E2
Embodiment 66: compound F 17-hydroxy-corticosterone-E3's is synthetic
Method is with embodiment 29, and different is to replace F-I2 with F-E2, obtains yellow solid.
Productive rate 66%:
1H NMR (400MHz, CDCl
3) δ 8.31 (d, J=8.8Hz, 2H), 7.88-7.80 (m, 2H), 7.70 (d, J=8.8Hz, 2H), 7.18 (d, J=7.9Hz, 1H), 4.31 (t, J=6.0Hz, 2H), 3.36-3.30 (m, 2H), 3.24 (t, J=6.0Hz, 4H), 1.82-1.73 (m, 4H), 1.69-1.62 (m, 2H); LC-MS m/z:421[M+H]
+.
Compound F 17-hydroxy-corticosterone-E3
Embodiment 67: compound F 17-hydroxy-corticosterone-E4's is synthetic
Method is with embodiment 30, and different is to replace F-I3 with F-E3, obtains yellow solid.
Productive rate 71%:1H NMR (400MHz, CDCl3) δ 7.81 (d, J=13.0Hz, 1H), 7.72 (s, 1H), 7.40 (d, J=8.5Hz, 1H), 7.17 (s, 1H), 6.72 (d, J=8.5Hz, 2H), 4.26 (t, J=6.0Hz, 1H), 3.95 (s, 1H), 3.28-3.18 (m, 3H), 1.80-1.73 (m, 2H), 1.67-1.61 (m, 1H); LC-MS m/z:391[M+H]
+.
Compound F 17-hydroxy-corticosterone-E4
Embodiment 68: compound F 17-hydroxy-corticosterone P-E1's is synthetic
Method is with embodiment 35, and different is to replace the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, and replaces F-I4 with F-E4, gets light yellow solid.
Productive rate 51%:1H NMR (400MHz, CDCl3) δ 11.50 (s, 1H), 7.79 (d, J=13.0Hz, 1H), 7.71 (t, J=2.4Hz, 1H), 7.57 (d, J=8.6Hz, 2H), 7.49 (d, J=8.7Hz, 2H), 7.13 (d, J=7.9Hz, 1H), 4.24 (t, J=8.0Hz, 2H), and 3.28-3.23 (m, 2H), 3.20 (t, J=6.0Hz, 4H), 2.88 (t, J=6.0Hz, 2H), 2.71 (s, 4H), 2.57 (t, J=4.0Hz, 2H), 1.92 (s, 4H), 1.79-1.72 (m, 4H), 1.66-1.60 (m, 2H); LC-MS m/z:516[M+H]
+.
Compound F 17-hydroxy-corticosterone P-E1
Embodiment 69: compound F 17-hydroxy-corticosterone P-E2's is synthetic
Method is with embodiment 35, and different is to replace the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, and replaces F-I4 with F-E4, and replaces Pyrrolidine with diethylamine, gets light yellow solid.
Productive rate 46%:
1H NMR (400MHz, CDCl
3) δ 11.48 (s, 1H), 7.79 (d, J=13.0Hz, 1H), 7.71 (s, 1H), 7.62 (d, J=8.6Hz, 2H), 7.49 (d, J=8.5Hz, 2H), 7.13 (d, J=7.9Hz, 1H), 4.24 (t, J=7.2Hz, 2H), 3.27-3.19 (m, 6H), 2.82 (t, J=4.0Hz, 2H), 2.71 (q, J=7.1Hz, 4H), 2.55 (t, J=6.0Hz, 2H), 1.78-1.73 (m, 4H), 1.66-1.60 (m, 2H), 1.16 (t, J=7.1Hz, 6H); LC-MS m/z:518[M+H]
+.
Compound F 17-hydroxy-corticosterone P-E2
Embodiment 70: compound F 17-hydroxy-corticosterone P-E3's is synthetic
Method is with embodiment 35, and different is to replace the 2-chloroacetyl chloride with the 3-chlorpromazine chloride, and replaces F-I4 with F-E4, and replaces Pyrrolidine with piperidines, gets light yellow solid.
Productive rate 47%:
1H NMR (400MHz, CDCl
3) δ 11.59 (s, 1H), 7.75 (d, J=13.0Hz, 1H), 7.68 (s, 1H), 7.60 (d, J=8.5Hz, 2H), 7.47 (d, J=8.5Hz, 2H), 7.11 (d, J=7.9Hz, 1H), 4.21 (t, J=7.2Hz, 2H), 3.24-3.16 (m, 6H), 2.68 (t, J=6.0Hz, 2H), 2.64-2.47 (m, 6H), and 1.77-1.68 (m, 8H), 1.64-1.53 (m, 4H); LC-MS m/z:530[M+H]
+.
Compound F 17-hydroxy-corticosterone P-E3
Table 1 compound when 10 μ mol/L to the active restraining effect of Telomerase
Embodiment 71: the described Quinzolone derivatives of this patent is to the restraining effect of Telomerase
Select the representative compound of part, adopt the TRAP method to carry out the cell-free system telomerase activity.From human breast cancer cell strain MCF-7, extract total protein (including Telomerase), a certain amount of total protein extracting solution and medicament mixed to be measured are added in the TRAP reaction mixture, utilize fluorescence gel imager or fluorescence microplate reader to detect after the PCR reaction, the result is as shown in table 1.The result shows when the described compound of this patent is 10 μ mol/L in concentration, external Telomerase is had obvious restraining effect.Therefore to can be used for preparing with the Telomerase be the cancer therapy drug of target spot to novel quinazoline ketone derivatives of the present invention.
Embodiment 72: the described Quinzolone derivatives of this patent is to the restraining effect of growth of tumour cell
Select the representative compound of part,, adopt mtt assay to carry out the cell in vitro poison and measure with two kinds of tumor cell line NCI-H460 (human lung adenocarcinoma cell line), GLC-82 (human lung adenocarcinoma cell line).The logarithmic phase cell adds the novel quinazoline ketone derivatives of different concns, acts on after 48 hours, measures its absorbancy.Calculate the compound concentration that cell growth inhibiting reaches at 50% o'clock respectively, with IC
50Value representation, the result is as shown in table 2.The result shows that the described compound of this patent all has stronger restraining effect external to these two kinds of tumor cell lines.Therefore Quinzolone derivatives of the present invention can be used for preparing anticancer medicine.
Embodiment 73: the described Quinzolone derivatives acute toxicity test of this patent
Select the representative compound (as FP-b2) of part, carry out acute toxicity test.Get 18-22 gram mouse and divide six groups at random, every group of 10 mouse, handle with physiological saline, DMSO 2.5ml/kg, FP-b2500mg/kg, FP-b2200mg/kg, FP-b2100mg/kg, FP-b250mg/kg respectively, observed 14 days, 45% death of the visible 500mg/kg group of result mouse, promptly FP-b2 is approximately 500mg/kg to the acute toxicity LD50 value of mouse.Therefore the acute toxicity of Quinzolone derivatives of the present invention is less, can be used for preparing cancer therapy drug.
Table 2 formula I compound is to the restraining effect (IC of tumor cell line growth
50/ μ M)
Claims (8)
1. Quinzolone derivatives is characterized in that structural formula is:
R in the formula
1Be F, Cl, Br or I;
R
2Be NH (CH
2)
nNR
4, NR
4Or NH (CH
2)
n-Ar;
R
3Be NHCO (CH
2)
nNR
4
M=1,2 or 3;
Wherein, n=1,2,3,4 or 5;-Ar is aromatic nucleus or aromatic heterocycle; R
4Group C
1-6Alkyl, C
3-6Cycloalkyl, piperidyl, morpholinyl, piperazinyl Huo Bi Evil quinoline base.
2. Quinzolone derivatives is characterized in that structural formula is:
R in the formula
1Be F, Cl, B or I;
R
2Be NH (CH
2)
nNR
4, NR
4Or NH (CH
2)
n-Ar;
R
3Be CONH (CH
2)
nNR
4
M=1,2 or 3;
Wherein, n=1,2,3,4 or 5;-Ar is aromatic nucleus or aromatic heterocycle; R
4Group is C
1-6Alkyl, C
3-6Cycloalkyl, piperidyl, morpholinyl, piperazinyl Huo Bi Evil quinoline base.
3. Quinzolone derivatives is characterized in that structural formula is:
R in the formula
1=H, R
2=R
3=NHCO (CH
2)
nNR
4; Perhaps R
2=H, R
1=R
3=NHCO (CH
2)
nNR
4
M=2 or 3;
Wherein, n=1,2,3,4 or 5, R
4Group is C
1-6Alkyl, C
3-6Cycloalkyl, piperidyl, morpholinyl, piperazinyl Huo Bi Evil quinoline base.
4. the preparation method of a Quinzolone derivatives as claimed in claim 1 is characterized in that:
When m=1, the preparation method may further comprise the steps: 4,5 2-benzaminic acid and pyrrolidone pass rings that two halogens replace obtain compound
Wherein X represents F, Cl, Br or I; With itself and HR
2Carry out substitution reaction, obtain compound
The phenyl aldehyde condensation that replaces with nitro obtains compound again
Obtain compound through reduction reaction again
The alkyl acyl chloride that itself and chlorine replace carries out alkylated reaction, again with NHR
4Reaction obtains Quinzolone derivatives, and structural formula is
When m=2 or 3, the preparation method may further comprise the steps: 4,5 2-benzaminic acid and various lactan pass rings that two halogens replace obtain compound
Wherein X represents F, Cl, Br or I; Phenyl aldehyde condensation with itself and nitro replace obtains compound
Obtain compound through reduction reaction again
Again with HR
2Substitution reaction takes place, and obtains compound
The alkyl acyl chloride that itself and chlorine are replaced carries out alkylated reaction again, again with NHR
4Reaction obtains Quinzolone derivatives, and structural formula is
5. the preparation method of a Quinzolone derivatives as claimed in claim 2, it is characterized in that: when m=1, the preparation method may further comprise the steps: 4, the 2-benzaminic acid that replaces of 5 two halogens is closed with pyrrolidone and is encircled, and obtains compound
Wherein X represents F, Cl, Br or I; Again with HR
2Substitution reaction takes place, and obtains chemical combination
With itself and the condensation of 4-carbamoyl benzoate, obtain compound
Again with itself and NH (CH
2)
nNR
4Reaction obtains Quinzolone derivatives, and structural formula is
When m=2 or 3, the preparation method may further comprise the steps: 4,5 2-benzaminic acid and pyrrolidone pass rings that two halogens replace obtain compound
Wherein X represents F, Cl, Br or I; With itself and the condensation of 4-carbamoyl benzoate, obtain compound
With itself and HR
2Substitution reaction takes place, and obtains compound
Again with itself and NH (CH
2)
nNR
4Reaction obtains Quinzolone derivatives, and structural formula is
6. the preparation method of a Quinzolone derivatives as claimed in claim 3 is characterized in that may further comprise the steps: the 2-benzaminic acid that 4 or 5 nitros replace is closed with various lactan and is encircled, and obtains compound
With its phenyl aldehyde condensation that replaces with nitro again, obtain compound
Obtain compound through reduction reaction again
The alkyl acyl chloride that itself and chlorine are replaced carries out after alkylated reaction obtains intermediate again, again with NHR
4Reaction obtains Quinzolone derivatives, and structural formula is
7. as the described preparation method of the arbitrary claim of claim 4～6, it is characterized in that the Quinzolone derivatives that described reaction obtains obtains pure product through column chromatography or recrystallization.
8. as the purposes of the described Quinzolone derivatives of the arbitrary claim of claim 1～3 in the preparation cancer therapy drug.
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Cited By (5)
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| CN102382064A (en) * | 2011-09-15 | 2012-03-21 | 中山大学 | Quinnazolidone derivative, preparation method for same and application thereof |
| CN106220631A (en) * | 2016-07-26 | 2016-12-14 | 中山大学 | A kind of 7 fluorine replace Isaindigotone derivant and preparation method thereof and the application in preparing cancer therapy drug |
| CN107522700A (en) * | 2017-08-03 | 2017-12-29 | 中山大学 | A kind of quinazolinone and α, the conjugated derivative of beta unsaturated ketone and its preparation method and application |
| CN109232576A (en) * | 2018-10-22 | 2019-01-18 | 信阳师范学院 | 7- replaces deoxidation malabar nut ketone alkali and its preparation method and application |
| CN114249733A (en) * | 2021-07-16 | 2022-03-29 | 兰州大学 | Isaindigotone derivative and application thereof in preparation of antitumor drugs |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102382064A (en) * | 2011-09-15 | 2012-03-21 | 中山大学 | Quinnazolidone derivative, preparation method for same and application thereof |
| CN102382064B (en) * | 2011-09-15 | 2014-01-15 | 中山大学 | Quinnazolidone derivative, preparation method for same and application thereof |
| CN106220631A (en) * | 2016-07-26 | 2016-12-14 | 中山大学 | A kind of 7 fluorine replace Isaindigotone derivant and preparation method thereof and the application in preparing cancer therapy drug |
| CN106220631B (en) * | 2016-07-26 | 2019-02-05 | 中山大学 | A kind of 7 fluorine replace Isaindigotone derivative and preparation method thereof and are preparing the application in anticancer drug |
| CN107522700A (en) * | 2017-08-03 | 2017-12-29 | 中山大学 | A kind of quinazolinone and α, the conjugated derivative of beta unsaturated ketone and its preparation method and application |
| CN107522700B (en) * | 2017-08-03 | 2020-03-20 | 中山大学 | Quinazolinone and α -unsaturated ketone conjugated derivative and preparation method and application thereof |
| CN109232576A (en) * | 2018-10-22 | 2019-01-18 | 信阳师范学院 | 7- replaces deoxidation malabar nut ketone alkali and its preparation method and application |
| CN109232576B (en) * | 2018-10-22 | 2020-07-17 | 信阳师范学院 | 7-substituted desoxypeganone base and preparation method and application thereof |
| CN114249733A (en) * | 2021-07-16 | 2022-03-29 | 兰州大学 | Isaindigotone derivative and application thereof in preparation of antitumor drugs |
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| Publication number | Publication date |
|---|---|
| CN101857595B (en) | 2012-11-21 |
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