CN102503908B - Vitamin A acid derivative, preparation method thereof, medicine composition thereof and application thereof to preparation anti-tumor medicine - Google Patents

Vitamin A acid derivative, preparation method thereof, medicine composition thereof and application thereof to preparation anti-tumor medicine Download PDF

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CN102503908B
CN102503908B CN 201110373722 CN201110373722A CN102503908B CN 102503908 B CN102503908 B CN 102503908B CN 201110373722 CN201110373722 CN 201110373722 CN 201110373722 A CN201110373722 A CN 201110373722A CN 102503908 B CN102503908 B CN 102503908B
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tretinoin
unsubstituted
preparation
substituted
acceptable salt
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CN102503908A (en
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王涛
李倩倩
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Wuxi Jiangyuan Industry Co Jiangsu Institute Of Nuclear Medicine
Jiangsu Institute of Nuclear Medicine
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Wuxi Jiangyuan Industry Co Jiangsu Institute Of Nuclear Medicine
Jiangsu Institute of Nuclear Medicine
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Abstract

The invention provides a vitamin A acid derivative with a general formula (I) as well as an isomer, a despinner, a diastereomer mixture, an external despinner mixture, a solvent compound, a polycrystal compound or pharmacy acceptable salt thereof. In the general formula (I), R represents H, substituted or unsubstituted C1 to C4 alkyl, substituted or unsubstituted C1 to C4 vinyl, substituted or unsubstituted alicyclic alkyl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaromatics and substituted or unsubstituted monosaccharide or polysaccharide groups, wherein the pharmacy acceptable salt comprises hydrochloride, hydrobromide, phosphate, lactate, tartrate, salicylate, sulfate, oxalate, acetate, succinate, maleate, malate, gluconate, p-toluenesulfonate, citrate, L-carnitine fumarate, formate and phenylpropionate. The invention also provides a preparation method, a medicine composition and an application of the vitamin A acid derivative. The vitamin A acid derivative has a good anti-tumor effect.

Description

Tretinoin derivative, its preparation method, its pharmaceutical composition and the application in the preparation antitumor drug thereof
Technical field
The present invention relates to a kind of tretinoin derivative, also relate to preparation method, its pharmaceutical composition and the application in the preparation antitumor drug thereof of this tretinoin derivative.
Background technology
Tretinoin and analogue thereof (retinoids) are retinoid derivatives, comprise tretinoin, N-(4-carboxyphenyl)retinamide, Viaminate and natural vitamin A etc., and kind more than 4000 is arranged approximately.It is sick as angling dermatoses, photoaging skin disease etc. that the tretinoin compound is widely used in treating various skin, but its most noticeable effect is to prevent and treat some malignant tumours, comprises mammary cancer, skin carcinoma, cervical cancer, leukemia etc.The scientific research personnel has carried out extensive, deep clinical study to the alltrans tretinoin in this compounds and 9-cis tretinoin.At present, the alltrans tretinoin has been used for treatment (Evans T R, Kaye S B, J Cancer, 1999,80 (1-2): 1-9) of malignant tumours such as acute promyelocytic leukemia, oral leukoplakia.The curative effect of 9-cis tretinoin is suitable with the alltrans tretinoin, also gets a good chance of becoming clinical medicine.
Figure 555538DEST_PATH_IMAGE001
Oneself is of a specified duration for the anticancer research origin of thiadiazole compound.Before more than 50 years, investigators focus on 2-amino-1,3 for the first time, on the anticancer research of 4-thiadiazoles (ATDA) and some simple derivatives thereof (as 2-ethylamino-1,3,4-thiadiazoles, amino couple-1,3 of 2,2-, two inferior A, 4-thiadiazoles).Studies show that much they all have the good anticancer activity, its mechanism of action and cell death inducing and inhibition associated angiogenesis.ATDA once was used for the II clinical trial phase in order to treat cancer (Joanna M and Adam O. Bioorganic ﹠amp such as kidney, colorectal carcinoma, ovarian cancer; Medicinal Chemistry, 2006,14:4483-4489).
Summary of the invention
The invention provides a kind of tretinoin derivative, tretinoin and thiadiazole compound are carried out coupling obtain, this tretinoin derivative can well be used for antitumor.The present invention also provides its pharmaceutical composition of preparation method and the application in the preparation antitumor drug thereof of this tretinoin derivative.
The invention provides tretinoin derivative and isomer, raceme, non-enantiomer mixture, raceme mixture, solvate, polycrystal thing or the pharmacy acceptable salt of following logical formula I to achieve these goals:
Figure 2011103737228100002DEST_PATH_IMAGE002
（Ⅰ）
Wherein R represents H, replacement or unsubstituted C 1-C 4Alkyl, replacement or unsubstituted C 1-C 4Thiazolinyl, replacement or unsubstituted alicyclic alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted monose or polysaccharide base;
Described pharmacy acceptable salt comprises hydrochloride, hydrobromate, phosphoric acid salt, lactic acid salt, tartrate, salicylate, vitriol, oxalate, acetate, succinate, maleate, malate, gluconate, tosilate, Citrate trianion, fumarate, formate and phenpropionate.
Further, described R represents to replace or unsubstituted C 1-C 4Alkyl.
Further, described R represents to replace or unsubstituted methyl.
Further, described R represents the tertiary butyloxycarbonyl ylmethyl.
Second purpose of the present invention provides the preparation method of the tretinoin derivative of logical formula I, may further comprise the steps:
In anhydrous dimethyl formamide, 2-amino-5-sulfydryl-1,3, the 4-thiadiazoles generates intermediate (1) with bromination R or iodate R under Anhydrous potassium carbonate catalysis, tretinoin and phosphorus trichloride effect generate dimension A acyl chlorides (2), dimension A acyl chlorides and intermediate (1) are under triethylamine (NEt3) catalysis, and room temperature reaction makes the tretinoin derivative of general formula (I).Its reaction scheme is as follows:
Wherein R represents H, replacement or unsubstituted C 1-C 4Alkyl, replacement or unsubstituted C 1-C 4Thiazolinyl, replacement or unsubstituted alicyclic alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted monose or polysaccharide base; X represents halogen.
The 3rd purpose of the present invention provides a kind of pharmaceutical composition, it comprises each described tretinoin derivative of claim 1-3 and isomer, raceme, non-enantiomer mixture, raceme mixture, solvate, polycrystal thing or the pharmacy acceptable salt for the treatment of effective dose, and acceptable accessories.
The 4th purpose of the present invention provides tretinoin derivative and the application in the preparation antitumor drug of isomer, raceme, non-enantiomer mixture, raceme mixture, solvate, polycrystal thing or pharmacy acceptable salt thereof.
Further, described tumor disease is liver cancer.
Embodiment
Preparation embodiment 1
(complete-trans)-3,7-dimethyl-9-(2,6,6-trimethyl cyclohexene)-2,4,6,8-nona tetraenoic acid 2-[(5-methylthio group)-1,3, the 4-thiadiazolyl group)] preparation of acid amides (I).
A) 2-amino-5-thiopurine methyltransferase-1,3, the preparation of 4-thiadiazoles.
Take by weighing 2.0g (14 mmoL) 2-sulfydryl-5-amino-1,3, the 4-thiadiazoles adds 20 mL dry DMF (dimethyl formamide), adds the 2.76g anhydrous K then 2CO 3, stirring at room 10min adds 2.82g (20 mmoL) methyl iodide at last, after continuing to react 4 h, stopped reaction is poured the 50ml frozen water in reaction solution, placement is spent the night, and the adularescent solid is separated out, suction filtration, filter cake dehydrated alcohol recrystallization gets white crystal 1.91g, yield 93%.mp：158～160℃。
B) preparation of dimension A acyl chlorides.
1.5g (5mmol) tretinoin and 20mL dry-out benzene are added in the 100mL three-necked bottle; in condition of ice bath, drip 0.3mL (10mmo1) phosphorus trichloride under the nitrogen protection, after dropwising, remove ice bath; stirring at room; tretinoin is dissolved in benzene gradually, and has dark red phosphorous acid precipitation to separate out, and solution manifests and finishes reaction when orange-yellow behind 2 h; solvent evaporated; get orange-yellow oily thing 0.9 g, keep in Dark Place yield 53.9%.
C) (complete-trans)-3,7-dimethyl-9-(2,6,6-trimethyl cyclohexene)-2,4,6,8-nona tetraenoic acid 2-[(5-methylthio group)-1,3, the 4-thiadiazolyl group)] preparation of acid amides.
With 2.0 g (10mmo1) 2-amino-5-thiopurine methyltransferase-1; 3; the 4-thiadiazoles; the triethylamine of 20mL anhydrous methylene chloride and catalytic amount adds in the 100 mL three-necked bottles; under cryosel bath and nitrogen protection, drip the solution that 1.7 g (5 mmo1) dimension A acyl chlorides and 20mL anhydrous diethyl ether are made into; dropwise; stirred overnight at room temperature; use the 5%(mass percent) dilute hydrochloric acid 20 mL washing 3 times; anhydrous sodium sulfate drying, solvent evaporated, column chromatography [V vinyl acetic monomer (ethyl acetate): V sherwood oil (petroleum ether)=3: 11] separates; get safran pulverulent solids 2.0 g, yield 54%.mp:82～85℃。ESI-MS(m/z)：430（[M+H] +）, 1H?NMR(400MHz，CHCl 3?dppm）：6.99?(d,?vinylic?H,?1H),?6.30(d,?vinylic?H,?1H),?6.28?(d,?vinylic?H,1H),?6.17?(s,?vinylic?H,?1H),?6.11?(d,?vinylic?H,1H),?5.79?(d,?vinylic?H,?1H),5.78?(s,?1H,?CONH)，3.42(s,?3H,?SCH 3)，1.03-2.40?(5s,?15H,5CH 3)。
Preparation embodiment 2
According to the preparation method of embodiment 1, prepare the tretinoin derivative of following general formula, use corresponding iodine aliphatic hydrocarbon or bromine aliphatic hydrocarbon.
A) (complete-trans)-3,7-dimethyl-9-(2,6,6-trimethyl cyclohexene)-2,4,6,8-nona tetraenoic acid 2-[(5-ethylmercapto group)-1,3, the 4-thiadiazolyl group)] acid amides (II).Productive rate, 45%, mp:78～80 ℃.ESI-MS(m/z)：444（[M+H] +）, 1H?NMR(400MHz，CHCl 3?dppm）：6.99?(d,?vinylic?H,?1H),?6.30(d,?vinylic?H,?1H),?6.28?(d,?vinylic?H,1H),?6.17?(s,?vinylic?H,?1H),?6.11?(d,?vinylic?H,1H),?5.79?(d,?vinylic?H,?1H),5.78?(s,?1H,?CONH)，3.35-3.39(m,?2H,?SCHB 2)，1.03-2.40?(6?s,?18H,6CHB 3)。
B) (complete-trans)-3,7-dimethyl-9-(2,6,6-trimethyl cyclohexene)-2,4,6,8-nona tetraenoic acid 2-[5-(tert-butoxycarbonyl ethylmercapto group)-1,3,4-thiadiazolyl group)] acid amides (III).Productive rate 20%, mp:70～72 ℃.ESI-MS(m/z)：530（[M+H] ?+） 1H?NMR(400MHz，CHCl 3?dppm）：6.99?(d,?vinylic?H,?1H),?6.30(d,?vinylic?H,?1H),?6.28?(d,?vinylic?H,1H),?6.17?(s,?vinylic?H,?1H),?6.11?(d,?vinylic?H,1H),?5.79?(d,?vinylic?H,?1H),5.78?(s,?1H,?CONH)，4.42(s,?2H,?SCH 2),2.81(s,?3H,?SCH 2)，1.03-2.40?(8?s,?24H,8CH 3)。
Antitumous effect embodiment
Blue colorimetry (MTT) antitumor activity in vitro of tetramethyl-nitrogen azoles.
Adopt the tetramethyl-nitrogen blue colorimetry of azoles (MTT) to estimate it to the antiproliferative activity of liver cancer cell in tretinoin derivative of the present invention.Mtt assay has been widely used in the responsive mensuration of large-scale screening anti-tumor medicine, cell toxicity test and tumour radiotherapy etc.Positive control drug is selected Zorubicin (ADR) and 4-HPR(4-hydroxy phenyl dimension A acid amides for use), ADR is widely used antitumor drug clinically at present.
Hepatoma cell strain: Hep G2.
Experimental technique is as follows: get and be in one bottle in cell in good condition exponential phase of growth, add 0.25% tryptic digestive juice, attached cell is come off, make every milliliter and contain 2 * 10 4～4 * 10 4The suspension of individual cell.Obtained cell suspension is inoculated on 96 orifice plates, and every hole 180 μ L put constant temperature CO 2Incubator was cultivated 24 hours.Change liquid, add test-compound (test-compound is respectively tretinoin derivatives I of the present invention, II, III and positive control drug) respectively, the preparation method with PBS(PBS after test-compound dissolves with dimethyl sulfoxide (DMSO) (DMSO) is: dissolving 8g NaCl, 0.2g KCl, 1.44g Na in 800ml distilled water 2HPO4 and 0.24 gram KH 2PO4, the pH value to 7.4 with the HCl regulator solution adds water and is settled to 1 liter) be diluted to 1 * 10 -7Mol/L, 1 * 10 -6Mol/L, 1 * 10 -5Mol/L), every hole adds 20 μ L, cultivates 48 hours.With 3-(4,5-dimethylthiazole-2)-2, (3-(4 for 5-phenylbenzene tetrazole bromine salt, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide is called for short MTT) MTT adds in 96 orifice plates, every hole 20 μ L, reaction is 4 hours in the incubator.Supernatant liquor is removed in suction, adds DMSO, every hole 150 μ L, and jolting is 5 minutes on the dull and stereotyped shaking table.With the optical density of enzyme-linked immunosorbent assay instrument in the every hole of test, wavelength 570nm place, calculate cell inhibitory rate.Cell inhibitory rate=(negative control group OD value-tried thing group OD value)/negative control thing OD value * 100%.Experimental result is as shown in table 1, and table 1 is retinoin anti-tumour cell proliferative activity (IC of the present invention 50, μ mol/L).
Figure 2011103737228100002DEST_PATH_IMAGE004
As can be seen from Table 1, tretinoin derivative of the present invention can good anti-liver cancer tumour, and better than tretinoin antitumous effect.When R was ester group in the tretinoin derivative of the present invention, effect was best.
Therefore, tretinoin derivative of the present invention can be made anti-tumor agent with hyoscine separately or with one or more pharmaceutically acceptable carrier combinations.For example, solvent, thinner etc.Can use the oral dosage form administration, but as tablet, capsule dispersed powders, granule etc.The various formulations of tretinoin derivative of the present invention can be prepared according to the method for knowing in the pharmaceutical field.
Tretinoin derivative of the present invention can with other tumour medicine such as alkylating agent (as endoxan or cis-platinum), antimetabolite (as 5 FU 5 fluorouracil or hydroxyurea), topoisomerase enzyme inhibitor (as camptothecine), mitotic inhibitor (as taxol or vinealeucoblastine(VLB)), DNA intercalating agent combined utilization such as (as Zorubicins), in addition can also with the radiation treatment combined utilization.These other antitumor drugs or radiation treatment can give with tretinoin derivative while of the present invention or different time.Thereby these combination therapys can produce synergy helps to improve result for the treatment of.
Because tretinoin can be used for prevention and treats mammary cancer, skin carcinoma, cervical cancer, leukemia, oral leukoplakia etc., and thiadiazoles can be used for treating kidney, colorectal carcinoma, ovarian cancer etc., therefore, can infer that the tretinoin derivative of the present invention that is obtained by tretinoin and thiadiazoles coupling also can be used for prevention and treat cancers such as mammary cancer, skin carcinoma, cervical cancer, leukemia, oral leukoplakia, kidney, colorectal carcinoma, ovarian cancer.
The above only is preferred embodiment of the present invention, and is in order to limit the present invention, within the spirit and principles in the present invention not all, any modification of doing, is equal to replacement, improvement etc., all should be included within protection scope of the present invention.

Claims (5)

1. tretinoin derivative and the pharmacy acceptable salt thereof of following logical formula I:
Figure 821309DEST_PATH_IMAGE001
（Ⅰ）
Wherein R represents methyl, ethyl, tertbutyloxycarbonyl ethyl or tertiary butyloxycarbonyl ylmethyl;
Described pharmacy acceptable salt comprises hydrochloride, hydrobromate, phosphoric acid salt, lactic acid salt, tartrate, salicylate, vitriol, oxalate, acetate, succinate, maleate, malate, gluconate, tosilate, Citrate trianion, fumarate, formate and phenpropionate.
2. the preparation method of the tretinoin derivative of a logical formula I may further comprise the steps:
In anhydrous dimethyl formamide, 2-amino-5-sulfydryl-1,3, the 4-thiadiazoles generates intermediate (1) with bromination R or iodate R under Anhydrous potassium carbonate catalysis, tretinoin and phosphorus trichloride effect generate dimension A acyl chlorides (2), dimension A acyl chlorides and intermediate (1) are under triethylamine catalysis, and room temperature reaction makes the tretinoin derivative of general formula (I);
Its reaction scheme is as follows:
Figure 216519DEST_PATH_IMAGE002
Wherein R represents methyl, ethyl, tertbutyloxycarbonyl ethyl or tertiary butyloxycarbonyl ylmethyl; X represents bromine or iodine.
3. pharmaceutical composition, it comprises the described tretinoin derivative of the claim 1 for the treatment of effective dose and pharmacy acceptable salt thereof, and acceptable accessories.
4. the described tretinoin derivative of claim 1 and pharmacy acceptable salt thereof the application in the preparation antitumor drug.
5. application according to claim 4 is characterized in that described tumor disease is liver cancer.
CN 201110373722 2011-11-22 2011-11-22 Vitamin A acid derivative, preparation method thereof, medicine composition thereof and application thereof to preparation anti-tumor medicine Expired - Fee Related CN102503908B (en)

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CN101605754A (en) * 2007-01-15 2009-12-16 于崇曦 Have the positively charged water soluble form of vitamin A acids of rapid skin penetration speed and the prodrug of retinoid acid compound

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