CN103396348B - Rorifone derivatives and applications to preparing anticancer medicaments - Google Patents
Rorifone derivatives and applications to preparing anticancer medicaments Download PDFInfo
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- CN103396348B CN103396348B CN201310367211.4A CN201310367211A CN103396348B CN 103396348 B CN103396348 B CN 103396348B CN 201310367211 A CN201310367211 A CN 201310367211A CN 103396348 B CN103396348 B CN 103396348B
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Abstract
The invention relates to rorifone derivatives and applications to preparing medicaments for treating lung cancer, liver cancer, breast cancer, pancreas cancer and intestinal cancer. The rorifone derivatives have a general formula shown in the specification, wherein R1 is SO (sulphoxide groupc) or SO2 (sulfuryl group), R2 is SCN (thiocyano group) or NCS (isothiocyano group), n=9-12. The invention relates to the applications of rorifone derivatives to preparing the medicaments for treating cancers.
Description
Technical field
She of the present invention is Ji the new derivative of Rorifone, and these new derivative application in the medicine preparing Therapeutic cancer.
Background technology
Chinese Patent Application No. 200310100945.2 discloses a kind of “ Rorifone dripping pill and preparation method thereof "; be make Rorifone dripping pill by application micronizing and pill production technology; raising disintegration can be reached and leach speed; onset is rapid; improve medicine stability; reduce supplementary product consumption, reduces production cost, object easy to carry and use.Compliance is good, is particularly suitable for children, the elderly, bed patient and dysphagia patients and takes.
Han dish is a kind of traditional herbal medicine, has the effect of anti-inflammatory, is used for the treatment of acute enteritis clinically, diarrhoea etc.This herbal medicine plants thing Han dish (Rorrippa Montana (wall) small) through qualification Shu Shizihua section, and distributed more widely in China, main chemical compositions is Rorifone (Rorifone).Tang Zongjian etc. report road Rorifone to be used for the treatment of chronic bronchitis clinically.
Summary of the invention
The object of this invention is to provide the derivative of the new compound — — Rorifone of a class.
The application of derivative in the medicine preparing Therapeutic cancer of another object of the present invention Shi Ti Gong Rorifone.
Traditional herbal medicine — — Han dish, has the effect of anti-inflammatory, is used for the treatment of chronic bronchitis in the prior art.Applicant Dui Rorifone carries out antitumor screening, in Mice Body in anti-Murine Hepatoma22 test, with 300mg/kg/d, 200mg/kg/d, 100mg/kg/d tri-dosage, oral administration 10 days, tumor control rate is respectively: 47.10%, 42.75%, 39.13%, Biao Ming Rorifone has obvious antitumour activity.The chemical structure of Rorifone is as follows:
In order to obtain the better compound of antitumour activity, the chemical structure of applicant Dui Rorifone is transformed, synthesized a series of new derivative, found that these compounds all have obvious antitumour activity through the anticancer test of pesticide effectiveness, its antitumour activity has exceeded the activity of Rorifone.
The chemical structure transformation of applicant Tong Guo Dui Rorifone, the derivative that He Cheng Chu Rorifone is new.
The derivative of Suo Shu Rorifone of the present invention, general structure is:
R in said structure
1for SO (sulfoxide group) or SO
2(sulfuryl), R
2for SCN (thiocyanogen) or NCS (isothiocyano), n=9 ~ 12.
The present invention relates to the application of derivative in the medicine preparing Therapeutic cancer of Suo Shu Rorifone.
Work as R
1for SO
2, R
2during for NCS, n=9, this compound is 1-isothiocyano-9-methylsulfonyl nonane, and following formula be shown in its chemical structural formula:
Work as R
1for SO, R
2during for SCN, n=9, this compound is 1-first sulfoxide group-9-thiocyanogen nonane, and following formula be shown in its chemical structural formula:
Work as R
1for SO, R
2during for NCS, n=12, this compound is 1-isothiocyano-12-first sulfoxide group dodecane, and following formula be shown in its chemical structural formula:
1-isothiocyano-9-methylsulfonyl nonane of the present invention, can prepare by the following method.
Preparation method: (concrete preparation method is shown in embodiment 1)
1, appropriate Rorifone and appropriate potassium hydroxide-ethanol solution (KOH/EtOH) hydrolysis reaction.
The product of 2, appropriate step 1 and the trimethyl carbinol (t-BuOH), diphenyl phosphate azide (DPPA) react.
Product and the hydrochloric acid/ethyl acetate (HCl/EA) of 3, appropriate step 2 are reacted.
The product of 4, appropriate step 3 and dithiocarbonic anhydride/Methanesulfonyl chloride (CS
2/ MSCl) be obtained by reacting 1-isothiocyano-9-methylsulfonyl nonane.
The physico-chemical property of 1-isothiocyano-9-methylsulfonyl nonane:
White powder, MP:59.6-60.6 DEG C, molecular formula: C
11h
21nO
2s
2, m/e:264 [M+H]
+, be dissolved in chloroform, ethyl acetate, water insoluble.
The present invention relates to the application of described 1-isothiocyano-9-methylsulfonyl nonane in the medicine of preparation treatment lung cancer, liver cancer, mammary cancer, carcinoma of the pancreas and intestinal cancer.
The anticancer pharmacodynamics test of 1-isothiocyano-9-methylsulfonyl nonane:
1, the pharmacy in vitro test of 1-isothiocyano-9-methylsulfonyl nonane:
1-isothiocyano-9-methylsulfonyl nonane is measured to 5 kinds of human tumor cell line: A549 (human lung carcinoma cell), SMMC-7721(human liver cancer cell) with mtt assay, MCF-7 (human breast cancer cell), PANC-1(human pancreatic cancer cell), HT-29(people's colon-cancer cell) IC
50.Test-results sees the following form 1.
Table 11-isothiocyano-9-methylsulfonyl nonane is to 5 kinds of human tumor cell line IC
50(μ g/ml)
As seen from Table 1, under this experiment condition, 1-isothiocyano-9-methylsulfonyl nonane demonstrates comparatively significantly killing action to human body tumour cell, but have comparatively significantly difference to the tumour cell of different tissue sources, prompting 1-isothiocyano-9-methylsulfonyl nonane has relative selectivity to different tumour cell.
2, the anti-Murine Hepatoma22 test of pesticide effectiveness in 1-isothiocyano-9-methylsulfonyl nonane Mice Body:
Sample is with 300mg/kg/d, 200mg/kg/d and/kg/d.To oral 1 time of mouse every day, the dosage regimen of continuous 10 times (ig × 10qd), carry out anti-Murine Hepatoma22 test in body, test-results is in table 2.
The anti-Murine Hepatoma22 test of pesticide effectiveness in table 21-isothiocyano-9-methylsulfonyl nonane Mice Body
3, the anti-intestinal cancer C-26 test of pesticide effectiveness in 1-isothiocyano-9-methylsulfonyl nonane Mice Body:
Sample is with 300mg/kg/d, 200mg/kg/d and 100mg/kg/d.To mouse gastric infusion every day 1 time, the dosage regimen of continuous 10 times (ig × 10qd), carry out the anti-intestinal cancer C-26 test of pesticide effectiveness in Mice Body, test-results is in table 3.
The anti-intestinal cancer C-26 test of pesticide effectiveness in table 31-isothiocyano-9-methylsulfonyl nonane Mice Body
4, the anti-Lewis lung cancer test of pesticide effectiveness in 1-isothiocyano-9-methylsulfonyl nonane Mice Body:
Sample is with 300mg/kg/d, 200mg/kg/d and 100mg/kg/d.To mouse gastric infusion every day 1 time, the dosage regimen of continuous 10 times (ig × 10qd), carry out the anti-intestines Lewis lung cancer test of pesticide effectiveness in Mice Body, test-results is in table 4.
The anti-Lewis lung cancer test of pesticide effectiveness in table 41-isothiocyano-9-methylsulfonyl nonane Mice Body
1-isothiocyano-9-methylsulfonyl nonane is by the above-mentioned anticancer test of pesticide effectiveness, test-results shows, 1-isothiocyano-9-methylsulfonyl nonane has obvious antitumour activity to lung cancer, liver cancer, mammary cancer, carcinoma of the pancreas and intestinal cancer, and the power of antitumour activity and the number of dosage have certain dose-effect relationship.
1-isothiocyano-9-methylsulfonyl nonane of the present invention is preparing the application in cancer therapy drug field, and its formulation comprises tablet, capsule, soft capsule, dripping pill, pill, pulvis, suspensoid and granule.
1-first sulfoxide group-9-thiocyanogen nonane of the present invention.Can prepare by the following method.
Preparation method: (concrete preparation method is shown in embodiment 2)
1,1,9-bis-appropriate bromononane and sodium methyl mercaptide/dimethyl formamide (CH
3sNa/DMF) react.
Product and the metachloroperbenzoic acid/methylene dichloride (m-MCPBA/DCM) of 2, appropriate step 1 react.
The product of 3, appropriate step 2 and potassium thiocyanate/chlorobenzene (KSCN/PhCl) are obtained by reacting 1-mono-first sulfoxide group-9-thiocyanogen nonane.
The physico-chemical property of 1-first sulfoxide group-9-thiocyanogen nonane:
Pale yellow oily liquid body, molecular formula: C
11h
21nOS
2, m/e:248 [M+H]
+, be dissolved in chloroform, ethyl acetate, water insoluble.
The present invention relates to the application of described 1-first sulfoxide group-9-thiocyanogen nonane in the medicine of preparation treatment lung cancer, liver cancer, mammary cancer, carcinoma of the pancreas and intestinal cancer.
The anticancer pharmacodynamics test of 1-first sulfoxide group-9-thiocyanogen nonane:
1, the pharmacy in vitro test of 1-first sulfoxide group-9-thiocyanogen nonane:
1-first sulfoxide group-9-thiocyanogen nonane is measured to 5 kinds of human tumor cell line: A549 (human lung carcinoma cell), SMMC-7721(human liver cancer cell) with mtt assay, MCF-7 (human breast cancer cell), PANC-1(human pancreatic cancer cell), HT-29(people's colon-cancer cell) IC
50.Test-results sees the following form 5.
Table 51-first sulfoxide group-9-thiocyanogen nonane is to 5 kinds of human tumor cell line IC
50(μ g/ml)
As seen from Table 5, under this experiment condition, 1-first sulfoxide group-9-thiocyanogen nonane demonstrates comparatively significantly killing action to human body tumour cell, but have comparatively significantly difference to the tumour cell of different tissue sources, prompting 1-isothiocyano-9-methylsulfonyl nonane has relative selectivity to different tumour cell.
2, the anti-Murine Hepatoma22 test of pesticide effectiveness in 1-first sulfoxide group-9-thiocyanogen nonane Mice Body:
Sample is with 300mg/kg/d, 200mg/kg/d and/kg/d.To oral 1 time of mouse every day, the dosage regimen of continuous 10 times (ig × 10qd), carry out anti-Murine Hepatoma22 test in body, test-results is in table 6.
The anti-Murine Hepatoma22 test of pesticide effectiveness in table 61-first sulfoxide group-9-thiocyanogen nonane Mice Body
3, the anti-intestinal cancer C-26 test of pesticide effectiveness in 1-first sulfoxide group-9-thiocyanogen nonane Mice Body:
Sample is with 30mg/kg/d, 20mg/kg/d and 10mg/kg/d.To mouse gastric infusion every day 1 time, the dosage regimen of continuous 10 times (ig × 10qd), carry out the anti-intestinal cancer C-26 test of pesticide effectiveness in Mice Body, test-results is in table 7.
The anti-intestinal cancer C-26 test of pesticide effectiveness in table 71-first sulfoxide group-9-thiocyanogen nonane Mice Body
4, the anti-Lewis lung cancer test of pesticide effectiveness in 1-first sulfoxide group-9-thiocyanogen nonane Mice Body:
Sample is with 30mg/kg/d, 20mg/kg/d and 10mg/kg/d.Every day oral administration 1 time, the dosage regimen of continuous 10 times (ig × 10qd), carry out anti-tumor in vivo clinical trial to Mice Bearing Lewis Lung Cancer, test-results is in table 8.
The anti-Lewis lung cancer test of pesticide effectiveness in table 81-first sulfoxide group-9-thiocyanogen nonane Mice Body
5,1-first sulfoxide group-9-thiocyanogen nonane is to the clinical trial to the human tumor lung cancer A549 transplanted in nude mice, liver cancer QGY:
Sample is with the dosage of 30mg/kg, 15mg/kg, 7.5mg/kg, oral 1 time of every day, the dosage regimen of continuous 14 times (ig × 14qd), respectively to transplanting in the human tumor lung cancer A549 of nude mice and doing the anticancer test of pesticide effectiveness to liver cancer QGY, test-results is in table 9 and table 10.
Table 91-first sulfoxide group-9-thiocyanogen nonane is to Human lung cancer A549 nude mice anticancer test
Table 101-first sulfoxide group-9-thiocyanogen nonane is to human hepatoma QGY nude mice anticancer test
1-first sulfoxide group-9-thiocyanogen nonane is by the above-mentioned test of pesticide effectiveness, test-results shows, 1-first sulfoxide group-9-thiocyanogen nonane has the antitumour activity of highly significant to lung cancer, liver cancer, mammary cancer, carcinoma of the pancreas and intestinal cancer, antitumour activity with have obvious dose-effect relationship to medicament.The antitumour activity contrast of He Rorifone, its antitumour activity has had and has significantly improved.
1-first sulfoxide group-9-thiocyanogen nonane of the present invention is preparing the application in cancer therapy drug field, and its formulation comprises tablet, capsule, soft capsule, dripping pill, pill, pulvis and suspensoid.
1-isothiocyano-12-first sulfoxide group dodecane of the present invention, can prepare by the following method.
Preparation method: (concrete preparation method is shown in embodiment 3)
1, appropriate 12－aminolauric acid and appropriate borane dimethylsulfide complex (BH
3.MeS) react.
The reaction product of 2, appropriate step 1 and two dimethyl dicarbonate butyl methyl esters ((BoC)
2o) react.
The reaction product of 3, appropriate step 2 and Methanesulfonyl chloride (MSCl) react.
The reaction product of 4, appropriate step 3 and sodium methyl mercaptide (NaSMe) react.
The reaction product of 5, appropriate step 4 and hydrochloric acid hydrolysis react.
The reaction product of 6, appropriate step 5 and dithiocarbonic anhydride (CS2) react.
The reaction product of 7, appropriate step 6 and metachloroperbenzoic acid (MCPBA) obtain 1-isothiocyano-12-first sulfoxide group dodecane.
The physico-chemical property of 1-isothiocyano-12-first sulfoxide group dodecane:
Pale yellow powder, MP:48.4-49.2 DEG C, molecular formula: C
14h
27nOS
2, m/e:290 [M+H]
+, be dissolved in chloroform, ethyl acetate, water insoluble.
The present invention relates to the application of described 1-isothiocyano-12-first sulfoxide group dodecane in the medicine of preparation treatment lung cancer, liver cancer, mammary cancer, carcinoma of the pancreas and intestinal cancer.
The anticancer pharmacodynamics test of 1-isothiocyano-12-first sulfoxide group dodecane:
1, the pharmacy in vitro test of 1-isothiocyano-12-first sulfoxide group dodecane:
1-isothiocyano-12-first sulfoxide group dodecane is measured to 5 kinds of human tumor cell line: A549 (human lung carcinoma cell), SMMC-7721(human liver cancer cell) with mtt assay, MCF-7 (human breast cancer cell), PANC-1(human pancreatic cancer cell), HT-29(people's colon-cancer cell) IC
50.Test-results sees the following form 11.
Table 111-isothiocyano-12-first sulfoxide group dodecane is to 5 kinds of human tumor cell line IC
50(μ g/ml)
As seen from Table 11, under this experiment condition, 1-isothiocyano-12-first sulfoxide group dodecane demonstrates comparatively significant killing action to human body tumour cell, but have comparatively significantly difference to the tumour cell of different tissue sources, prompting 1-isothiocyano-9-methylsulfonyl nonane has relative selectivity to different tumour cell.
2,1-isothiocyano-12-first sulfoxide group dodecane is to rat liver cancer H22 anti-tumor in vivo clinical trial:
Sample is with 300mg/kg/d, 200mg/kg/d and 100mg/kg/d.Oral 1 time of every day, the dosage regimen of continuous 10 times (ig × 10qd), carry out anti-tumor in vivo clinical trial to rat liver cancer H22 solid tumor, test-results is in table 12.
Table 121-isothiocyano-12-first sulfoxide group dodecane is to rat liver cancer H22 anti-tumor in vivo clinical trial
3,1-isothiocyano-12-first sulfoxide group dodecane is to mouse intestinal cancer C-26 anti-tumor in vivo clinical trial:
Sample is with 30mg/kg/d, 20mg/kg/d and 10mg/kg/d.Every day oral administration 1 time, the dosage regimen of continuous 10 times (ig × 10qd), carry out anti-tumor in vivo clinical trial to mouse intestinal cancer C-26, test-results is in table 13.
Table 131-isothiocyano-12-first sulfoxide group dodecane is to mouse intestinal cancer C-26 anti-tumor in vivo clinical trial
4,1-isothiocyano-12-first sulfoxide group dodecane is to Mice Bearing Lewis Lung Cancer anti-tumor in vivo clinical trial:
Sample is with 30mg/kg/d, 20mg/kg/d and 10mg/kg/d.Every day oral administration 1 time, the dosage regimen of continuous 10 times (ig × 10qd), carry out anti-tumor in vivo clinical trial to Mice Bearing Lewis Lung Cancer, test-results is in table 14.
Table 141-isothiocyano-12-first sulfoxide group dodecane is to Mice Bearing Lewis Lung Cancer anti-tumor in vivo clinical trial
1-isothiocyano-12-first sulfoxide group dodecane is by the above-mentioned antitumor test of pesticide effectiveness, test-results shows, 1-isothiocyano-12-first sulfoxide group dodecane has obvious antitumour activity to lung cancer, liver cancer, mammary cancer, carcinoma of the pancreas and intestinal cancer, and the power of antitumour activity and the number of dosage have certain dose-effect relationship.
1-isothiocyano-12-first sulfoxide group dodecane of the present invention is preparing the application in cancer therapy drug field, and its formulation comprises tablet, capsule, soft capsule, dripping pill, pill, pulvis and suspensoid.
Embodiment
The synthesis of embodiment 1:1-isothiocyano-9-methylsulfonyl nonane:
(1) in 500mL there-necked flask, under magnetic agitation, add 10.0g Rorifone, be suspended in 100ml, in the 10N KOH aqueous solution, then add 200ml EtOH, mix.Heating, to reaction system backflow, T=85 ~ 90 DEG C.Back flow reaction is spent the night, 18 ~ 20 hours.TLC follows the tracks of, without raw material.Concentrated, add 100ml H2O again in resistates, then adjust pH=5 ~ 6 with concentrated hydrochloric acid, stir 0.5 hour.Filter, filter cake washes with water, obtains crude product A.White solid A:10.0g is obtained, yield: 92.5% by dry for crude product.The Spectrum Analysis data of compd A:
1h NMR (400MHz, CDCl
3)
: 3.02 (t, J=8.0Hz, 2H, H-2), 2.91 (s, 3H, H-1), 2.36 (t, J=7.6Hz, 2H, H-10), 1.85 (m, 2H, H-3), 1.65 (m, 2H, H-9), 1.46 (m, 2H, H-4), 1.32 (m, 8H, H-5,6,7,8) .MS m/z (
+eSI): 251.3 ([M+H]
+, 100%).
(2) at 500mL there-necked flask, argon shield, under magnetic agitation, adds 10.0g compd A and is dissolved in 80ml DMF, add 16.7ml triethylamine, then add 114.7ml t-BuOH and 13.4mlDPPA, argon shield, stirs.Reaction heating, rises to 100 DEG C, has a large amount of bubble to overflow; To bubble-free, oil bath rises to 115-120 DEG C, heats TLC monitoring in 6-7 hour, without raw material, concentrated, add 200ml water and 200mlEA in resistates, stir 15 minutes, layering, aqueous phase uses 100mlEA extracting twice again, merges organic phase, respectively washes one time with 200ml water and saturated aqueous common salt.Organic phase concentrates, and crosses silica column purification, obtains faint yellow solid B, 7.8g, yield: 60.9%.Compd B Spectrum Analysis data:
1h NMR (400MHz, CDCl
3) δ ppm:3.11 (m, 2H, H-10), 3.02 (t, J=8.0Hz, 2H, H-2), 2.91 (s, 3H, H-1), 1.85 (m, 2H, H-3), 1.65 (m, 2H, H-9), 1.46 (m, 10H, H-4,5,6,7,8), 1.29 (m, 9H, H-Boc) .MSm/z (+ESI): 266.2 ([(M-56)+H]
+, 100%).
(3) 250mL single port bottle, under magnetic agitation, adds 7.5g compd B and 50ml3N Hydrochloride/ethyl acetate, it is very fast that reaction is carried out, and has bubble to emerge, under nitrogen protection, stirring at room temperature 1 hour, TLC detects does not have raw material, carefully boils off ethyl acetate, obtain pink solid, in solid, add 50ml TBME, ultrasonic cleaning, leave standstill 1 hour, pour out supernatant liquid, then add 50mlTBME, ultrasonic cleaning, leaves standstill 1 hour, pours out supernatant liquid; Concentrated, dry, obtain white solid, 5.8g, Compound C, yield: 96.6%.Compound C Spectrum Analysis data: H NMR (400MHz, DMSO) δ ppm:3.08 (t, J=8.0Hz, 2H, H-2), 2.94 (s, 3H, H-1), 2.75 (m, 2H, H-10), 1.65 (m, 2H, H-9), 1.54 (m, 2H, H-3), 1.36 (m, 2H, H-8), 1.27 (m, 8H, H-4,5,6,7) .MS m/z (+ESI): 222.3 ([M+H]
+, 100%).
(4) 500mL single port bottle, under magnetic agitation, adds 5.8g Compound C and is suspended in 100ml anhydrous tetrahydro furan, add 11.0ml triethylamine, after reaction solution ice-water bath is cooled to 0 DEG C, be added dropwise to 1.4ml dithiocarbonic anhydride, within about 20 minutes, drips off.After dropwising, rise to room temperature, and stirring at room temperature 1.5 hours, after then reaction solution ice-water bath is cooled to 0 DEG C, be added dropwise to 1.9ml Methanesulfonyl chloride, within about 5 minutes, drip off, after dropwising, rise to room temperature, stir 1 hour, obtain yellow suspension.The dilute hydrochloric acid of 100ml1N is added in reaction solution, after boiling off tetrahydrofuran (THF), add 150ml TBME, stir 15 minutes, layering, organic layer 100*3ml saturated salt washes three times, methyl tertiary butyl ether is boiled off after organic phase anhydrous sodium sulfate drying, crude product carries out column chromatography, and drying obtains 5.4g target compound, 1-isothiocyano-9-methylsulfonyl nonane.Yield 91%.
The Spectrum Analysis data of 1-isothiocyano-9-methylsulfonyl nonane:
1H NMR(400MHz,CDCl
3)δppm:3.52(t,J=6.4Hz,2H,H-10),3.02(t,J=8.0Hz,2H,H-2),2.91(s,3H,H-1),1.87(m,2H,H-9),1.70(m,2H,H-3),1.45(m,4H,H-4,8),1.35(m,6H,H-5,6,7).MS m/z(+ESI):264.1([M+H]
+,100%).HPLC:RT=20.79min(97.6%240nm).
The physico-chemical property of 1-isothiocyano-9-methylsulfonyl nonane:
White powder, MP:59.6-60.6 DEG C, molecular formula: C11H21NO2S2, M/Z:264 [M+H]
+, be dissolved in chloroform, ethyl acetate, water insoluble.
The synthesis of embodiment 2:1-first sulfoxide group-9-thiocyanogen nonane:
(1) in the single port bottle of 100ml, 8.5g1,9-bis-bromononane join in the DMF of 24mL.Reaction solution is cooled to zero degree, drips the sodium methyl mercaptide aqueous solution of 6ml40%, stirs after 0.5 hour, stirred overnight at room temperature, TLC shows raw material general about 10%, below raw material, have 2 new points, that leans on is very near, and wherein first point is compd A, and nethermost is two replacement by products.Pure PE crosses column chromatography, obtains 4.5g colourless oil liquid, compd A.The spectral data of compd A:
1h NMR (400MHz, CDCl
3)
: 3.40 (t, J=2.8Hz, 2H, C
h 2), 2.48 (t, J=3.4Hz, 2H, C
h 2), 2.08 (s, 3H, C
h 3), 1.85 (m, 2H, C
h 2), 1.61-1.53 (m, 2H, C
h 2), 1.36-1.29 (m, 9H, C
h 2).
(2) in the single port bottle of 25ml, 100mg compd A is dissolved in 5ml DCM, adds the m-CPBA of 75mg.After reaction stirring at room temperature 2h, LCMS shows product and generates.Add the Na2SO3 solution stirring 0.5h of 3ml, at the Na with 2ml
2cO
3the aqueous solution is washed.The white solid of 76mg is obtained, compd B after organic layer concentrates.The spectral data of compd B:
1h NMR (400MHz, CDCl
3) δ ppm:3.40 (t, J=6.8Hz, 2H, C
h 2), 2.81-2.60 (m, 2H, C
h 2), 2.58 (s, 3H, CH
3), 1.88-1.78 (m, 2H, C
h 2), 1.75-1.73 (m, 2H, C
h 2), 1.49-1.32 (m, 9H, C
h 2).
(3) in the single port bottle of 10ml, add 70mg compd B, the DIPEA of 18-crown-6 and 0.14ml of 76mg KSCN, 14mg, then add 3ml chlorobenzene, reaction solution intensification 100C stirs 3h, LCMS display product and generates, and raw material consumption is complete.After solvent is spin-dried for, with the acetic acid ethyl dissolution of 10ml, cross column chromatography after washing, obtain 20mg pale yellowish oil liquid, target compound 1-first sulfoxide group-9-thiocyanogen nonane.
The spectral data of 1-first sulfoxide group-9-thiocyanogen nonane:
1H NMR(400MHz,CDCl
3)δppm:2.86(t,J=3.2Hz,2H,C
H 2),2.64-2.54(m,2H,C
H 2),2.48(s,3H,C
H 3),1.76-1.65(m,4H,C
H 2),1.35-1.24(m,9H,C
H 2).M/Z:248[M+H]
+。
The physico-chemical property of 1-first sulfoxide group-9-thiocyanogen nonane:
Pale yellow oily liquid body, molecular formula: C
11h
21nOS
2, m/e:248 [M+H]
+, be dissolved in chloroform, ethyl acetate, water insoluble.
The synthesis of embodiment 3:1-isothiocyano-12-first sulfoxide group dodecane:
(1) in 100ml there-necked flask, 10.00g12-aminoundecane-earboxylic acid is suspended in 50ml tetrahydrofuran (THF).Reaction flask argon replaces 3 times, then adds 18.6ml borane dimethylsulfide complex.Be heated to 80 DEG C of backflows spend the night.After LCMS detection reaction is complete, reactant is cooled to room temperature, drips the glacial acetic acid methanol solution of 25ml20% under ice-water bath cooling.Stirred at ambient temperature is after 1 hour, pressure reducing and steaming solvent.Repeatedly add 30ml methyl alcohol (repeating 3 times) underpressure distillation subsequently except desolventizing.Add the 9M aqueous hydrochloric acid of 20ml water and 40ml in last residuum, stirring is spent the night.The white solid that collecting by filtration produces, and use a small amount of water washing, obtain 12.0g white solid after vacuum-drying, compd A.The Spectrum Analysis data of compd A:
1h NMR [400MHz, CDCl3/CD3OD (5:1)] δ ppm:5.51 (br s, 1H ,-OH), 3.46 (t, J=6.4Hz, 2H, H-1), 2.78 (t, J=7.2Hz, 2H), 1.52 (t, m, 2H), 1.43 (m, 2H), 1.17 (m, 16H).
(2) 3.91g sodium hydroxide is dissolved in the mixture (volume ratio is 1/1) of 80ml water and the trimethyl carbinol.After being cooled to room temperature, under agitation add 12.00g compd A and 10.66g (Boc) respectively
2o.Reactant room temperature for overnight, then with the dilution of 100ml1M dilute hydrochloric acid, stirs after 5 minutes, uses 60mL extraction into ethyl acetate twice respectively.Merge organic layer, anhydrous sodium sulfate drying, concentrate to obtain 12.21g white solid, compd B, yield 87.2%.The Spectrum Analysis data of compd B:
1h NMR (400MHz, CDCl3) δ ppm:4.50 (br s, 1H, NH), 3.63 (t, J=6.4Hz, 2H), 3.10 (t, J=6.4Hz, 2H), 1.59 ~ 1.52 (m, 2H), 1.43 (m, 11H), 1.33 ~ 1.26 (m, 16H).
(3) in 250ml there-necked flask, 12.2g compd B is dissolved in 60ml methylene dichloride, and adds 8.5ml triethylamine.After this solution ice-water bath is cooled to 0 DEG C, under lower than the condition of 5 DEG C, be added dropwise to 4.2ml Methanesulfonyl chloride.After dropwising, at room temperature stir 4 hours, then with the dilution of 50ml water, and stir 10 minutes.Isolate water layer, and use 40ml dichloromethane extraction.Merge organic layer, with steaming vibrating dichloromethane after anhydrous sodium sulfate drying, obtain 14.68g white solid, Compound C.Yield 95.1%.The Spectrum Analysis data of Compound C:
1h NMR (400MHz, CDCl3) δ ppm:4.49 (br s, 1H, NH), 4.23 (t, J=6.8Hz, 2H), 3.12 (t, J=6.4Hz, 2H), 3.00 (s, 3H), 1.78 ~ 1.71 (m, 2H), 1.44 ~ 1.35 (m, 13H), 1.26 (m, 14H).
(4) 100mL there-necked flask, under magnetic agitation, adds 14.68g Compound C dissolving crude product in 40ml DMF, and is cooled to 0 DEG C at ice-water bath.The sodium methyl mercaptide aqueous solution of 14.5ml20% is added dropwise to below 15 DEG C.After dropwising, room temperature for overnight.Then in reaction solution, 25mL water and 25ml methyl tertiary butyl ether is added.Stir after 15 minutes, layering, the extraction of water layer 60ml methyl tertiary butyl ether once merges organic layer afterwards.Organic layer 20ml washes once, boils off methyl tertiary butyl ether and obtain 12.25g white solid, Compound D after anhydrous sodium sulfate drying.Yield 94.4%.The Spectrum Analysis data of Compound D:
1h NMR (400MHz, CDCl
3) 4.51 (br s, 1H, NH), 3.20 (t, J=6.4Hz, 2H), 2.49 (t, J=7.2Hz, 2H), 2.08 (s, 3H), 1.61 ~ 1.53 (m, 2H), 1.48 (m, 11H), 1.35 (m, 2H), 1.24 (m, 14H).
(5) in 250ml single port bottle, at 0 DEG C, 12.25g Compound D is dissolved in 100ml2N Hydrochloride/ethyl acetate.Room temperature for overnight, TLC detects raw material and disappears.The solid that collecting by filtration generates, and wash by a small amount of ethyl acetate, obtain 9.10g white solid after drying, compd E, yield 93.7%.Compd E Spectrum Analysis data:
1h NMR (400MHz, CD
3oD) δ ppm:2.92 (t, J=7.6Hz, 2H), 2.49 (t, J=7.2Hz, 2H), 2.05 (s, 3H), 1.66 ~ 1.56 (m, 4H), 1.37 ~ 1.31 (m, 16H).
(6) in 250mL single port bottle, 6.00g compd E is dissolved in 110ml anhydrous tetrahydro furan, adds 21.8ml triethylamine, and in ice-water bath, be cooled to 0 DEG C.Slow dropping 4.1ml dithiocarbonic anhydride, drips off for about 10 minutes.Then stirring at room temperature 4 hours, is warming up to 40 DEG C of reactions 2 hours subsequently.After reaction solution ice-water bath is cooled to 0 DEG C, then be added dropwise to 5.7ml Methanesulfonyl chloride, within about 10 minutes, drip off.After dropwising, rise to stirred overnight at room temperature, be heated to 45 DEG C of reactions 2 hours subsequently.After question response liquid is down to room temperature, filter, a small amount of THF of solid washs.After filtrate is concentrated, crude product carries out column chromatography purification, obtains 5.84g deep yellow oily product, compound F 17-hydroxy-corticosterone, yield 94.8%.The Spectrum Analysis data of compound F 17-hydroxy-corticosterone:
1h NMR (400MHz, CDCl
3) δ ppm:3.51 (t, J=6.4Hz), 2.49 (t, J=7.2Hz, 2H), 2.08 (s, 3H, H-13), 1.70 ~ 1.65 (m, 2H), 1.60-1.54 (m, 2H), 1.42-1.26 (m, 16H).
(7), in 250ml there-necked flask, 5.80g compound F 17-hydroxy-corticosterone is dissolved in 60ml methylene dichloride, and after being cooled to 0 DEG C with ice-water bath.Be added dropwise to 4.76g77% metachloroperbenzoic acid and be dissolved in solution in 50ml methylene dichloride, and control temperature is not higher than 5 DEG C.After dropwising, stirred overnight at room temperature, it is complete that TLC detects raw material reaction.Add 70ml saturated sodium bicarbonate aqueous solution in reaction solution, stir 15 minutes, layering, water layer 50ml dichloromethane extraction.Merge organic phase, with the water washing of 100ml saturated common salt, steaming vibrating dichloromethane after anhydrous sodium sulfate drying.Residuum carries out column chromatography purification, obtains 5.15g light yellow solid, 1-isothiocyano-12-first sulfoxide group dodecane.Yield 83.9%.
The Spectrum Analysis data of 1-isothiocyano-12-first sulfoxide group dodecane:
1H NMR(400MHz,DMSO-d
6)δppm:3.66(t,J=6.4Hz,2H),2.72(m,1H),2.65(m,1H),2.50(d,J=2.0Hz,3H),1.64(m,4H),1.38-1.26(m,16H);
13C NMR(100MHz,DMSO-d
6)δppm:127.35,53.19,44.70,40.14,38.03,29.19,28.90,28.85,28.82,28.65,28.13,28.12,25.92,21.92.LC-MS(+ESI)m/e:290.2([M+H]
+,100%),579.4([2M+H]
+,90%)。
The physico-chemical property of 1-isothiocyano-12-first sulfoxide group dodecane:
Pale yellow powder, MP:48.4-49.2 DEG C, molecular formula: C
14h
27nOS
2, m/e:290 [M+H]
+, be dissolved in chloroform, ethyl acetate, water insoluble.
With above-mentioned 1-isothiocyano-9-methylsulfonyl nonane, 1-first sulfoxide group-9-thiocyanogen nonane and 1-isothiocyano-12-first sulfoxide group dodecane for monomer component, conveniently technique makes tablet, capsule, soft capsule, dripping pill, pill, pulvis and suspensoid, is used for the treatment of lung cancer, liver cancer, mammary cancer, carcinoma of the pancreas and intestinal cancer.
Claims (1)
1. the derivative of Yi Zhong Rorifone, is characterized in that structural formula is:
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| WO2013067040A1 (en) * | 2011-10-31 | 2013-05-10 | The Johns Hopkins University | Methods and compositions for treatment of autism |
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