CN101289421A - Method for synthesizing nicotinyl amino acids and sensitizing effect thereof to tumor radiotherapy - Google Patents

Method for synthesizing nicotinyl amino acids and sensitizing effect thereof to tumor radiotherapy Download PDF

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CN101289421A
CN101289421A CNA2007100571690A CN200710057169A CN101289421A CN 101289421 A CN101289421 A CN 101289421A CN A2007100571690 A CNA2007100571690 A CN A2007100571690A CN 200710057169 A CN200710057169 A CN 200710057169A CN 101289421 A CN101289421 A CN 101289421A
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nicotinoyl
acid
cancer
compound
amino acids
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李美佳
蒋铁南
荘湘莲
刘晓秋
王荣先
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Institute of Radiation Medicine of CAMMS
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Abstract

The invention provides a nicotinoyl amino compound with a general formula I or acceptable salts in pharmacy thereof. While the maternal structure of niacinammide is maintained, compounds such as amino monoacid and amino dibasic acid, etc., are introduced into a side chain of the niacinammide; radiotherapy sensitivity experiments on tumors show that the synthesized compounds all have sensitivity effects of different degrees. The invention also provides the series compound with the general formula I or acceptable salts in pharmacy thereof, which can be used as an effective component in application of preparing the radiotherapy sensitivity drugs for curing liver cancer, lung cancer, cervical cancer, breast cancer, lymph cancer and nasopharyngeal carcinoma.

Description

The synthetic method of nicotinoyl amino acids and to the sensitization of tumor radiotherapy
Technical field
The invention belongs to medical technical field, or rather, the present invention relates to nicotinoyl amino acids and preparation method thereof and the pharmaceutical composition that contains them, and this compounds is to the application of liver cancer, lung cancer, cervical cancer, mammary cancer, lymphatic cancer, nasopharyngeal carcinoma radiotherapy sensitization.
Background technology
Malignant tumour is a big class disease of serious threat human health, and its paraplasm is that unusual information is controlled in the cell, and is closely related with the Showed Very Brisk and the inactivation of corresponding gene in the tumour cell.Radiotherapy is the main means of treatment malignant tumour, also is in the treatment, one of the important means of late tumor.But, in killing tumor cell, also kill and wound normal cell in a large number, so toxic side effect is very big in the therapeutic process because the radioactive rays that adopted do not possess special selectivity to tumour cell.The radiosensitivity that how to increase tumour is the problem of being paid close attention in the tumour radiotherapy field always.
The existence of anoxic cell has limited the curative effect of gamma ray therapy tumour in the tumour, because these anoxic cells to the susceptibility of ray than the low 2-3 of aerobic cell doubly.After hamster cell is subjected to x-ray bombardment among the discovery V79 such as Ber-Hur, with the lethality that can strengthen ray after the niacinamide cultivation, the integral experiment tumour also there is radiosensitizing effect preferably, its enhanced sensitivity is 1.2-1.7 than (SER), and be 1.1-1.2 to the SER of little intestinal crypts of healthy tissues and skin, reference (1) Adams.G.E.The clinical relevanceof tumor hypoxia.Eur.J.Cancer 1990,26,420. (2) Dische, S.Hypoxia andLocal tumor control Part2.Radiother Oncol 1991,26,420 (3) Horsman, M.R, Chaplin, D.J.Radiosentization by nicotinamide in vivo:A greaterenhancement of tumor damage compared to that of normal tissues.Radiat.Res.1987,109,479.
Summary of the invention
The nicotinamide compound of our design, the precursor structure that has not only kept niacinamide, and introduce compounds such as amino monoprotic acid, dibasic amino acid at its side chain, radio therapy sensitization experiment to tumour shows, institute's synthetic compound all has radiosensitizing effect in various degree, and its mechanism is considered to strengthen the microcirculation of tumour, improves the supply of oxygen and the oxygenation of tumour, prevent the acute weary oxygen of tumour, thereby improve the lethality of ray tumour.
First purpose of the present invention is, discloses the structural formula of nicotinoyl amino acids or its pharmacy acceptable salt.The radio therapy sensitization effect of nicotinoyl amino acids to lung cancer, liver cancer, mammary cancer, cervical cancer, lymphatic cancer or nasopharyngeal carcinoma further disclosed simultaneously.
Second purpose of the present invention is, the pharmaceutical composition that tumor radiotherapy is had sensitization is provided, and it comprises the combination as the nicotinoyl amino acids of activeconstituents or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers, vehicle or thinner.
The 3rd purpose of the present invention is to provide the preparation method who tumor radiotherapy is had the nicotinoyl amino acids of sensitization.
The 4th purpose of the present invention has been to disclose known compound nicotinoyl Padil, nicotinoyl alanine, nicotinoyl aminobutyric acid, nicotinoyl aminovaleric acid, nicotinoyl aspartic acid, nicotinoyl 2-aminobutyric acid, nicotinoyl iminodiethanoic acid, nicotinoyl imino-diacetic propionic acid or nicotinoyl imino-diacetic butyric acid in preparation with as the application aspect the tumor radiotherapy enhanced sensitivity.The preparation method who is different from prior art of known compound is further disclosed simultaneously.
Concrete technical scheme of the present invention is as follows:
The present invention relates to have compound or its pharmacy acceptable salt of following formula structure
Wherein, R is-NHR 1COOH;-N (R 2COOH) 2-NH (R 3COOH) 2-NH-R 4(R 5)-COOH
R 1Be C1-C6 straight or branched alkyl;
R 2Be the C1-C4 straight chained alkyl;
R 3-5Be the C1-C3 straight chained alkyl;
The preferred compound of the present invention, wherein R 1Be C1-C4 straight or branched alkyl, R 2Be the C1-C4 straight chained alkyl; R 3-5Be the C1-C3 straight chained alkyl.
C1-C6 straight or branched alkyl of the present invention comprises: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, Skellysolve A, isopentyl or the like.The C1-C4 straight chained alkyl comprises: methyl, ethyl, propyl group, butyl, sec.-propyl or the like.The C1-C3 straight chained alkyl comprises: methyl, ethyl, propyl group.
Compound or its pharmacy acceptable salt with formula I structure of the present invention, wherein part of compounds is:
01. nicotinoyl Padil; 02 nicotinoyl alanine; 03 nicotinoyl aspartic acid; 04 nicotinoyl-2-aminobutyric acid; 05 nicotinoyl aminobutyric acid; 06 nicotinoyl aminovaleric acid; 07 nicotinoyl iminodiethanoic acid; 08 nicotinoyl imino-diacetic propionic acid; 09 nicotinoyl imino-diacetic butyric acid or its pharmacy acceptable salt.The amino oxalic acid of nicotinoyl, (dipropionic acid, two butyric acid) do not appear in the newspapers.
Nicotinoyl amino acids of the present invention or its pharmacy acceptable salt are meant the salt that they can form with conventional alkali, for example basic metal (for example sodium salt or sylvite), alkaline-earth metal (for example calcium and magnesium salts) or derived from the ammonium salt of ammonia or organic amine.Particular certain cancers and sylvite.
Amino acid of the present invention comprises: arginine, glycine, leucine, Methionin, Serine, phenylalanine, aspartic acid, L-Ala or the like.
The preparation method of nicotinoyl amino acids of the present invention is characterized in that, in the polar reaction solvent, amino acid and nicotinoyl nitrine is blended in 0-50 ℃, reacts 8-14 hour, carries out acylation reaction, makes the nicotinoyl amino acids; The ratio of weight and number of amino acid wherein and nicotinoyl nitrine is 1-5: 1.Polar reaction solvent wherein is water, ethanol, methyl alcohol or Virahol.
Conventional preparation technology adopts amino acid and nicotinoyl chlorine to react, and this reaction yield is low, and acyl chlorides is strong to the pungency of respiratory tract, the post-reaction treatment difficulty.Preparation technology of the present invention mixes amino acid to carry out acylation reaction with the nicotinoyl nitrine, have simple to operate, yield height, the characteristics of the good product purity that obtains.
The synthetic route of nicotinoyl amino acids of the present invention is as follows:
Figure A20071005716900071
In another aspect of this invention, provide the pharmaceutical composition that comprises that described nicotinoyl amino acids and pharmaceutically acceptable carrier are formed.
The present invention preferably provides a kind of has the pharmaceutical composition of sensitization to tumor radiotherapy, and it comprises the nicotinoyl amino acids for the treatment of significant quantity or the combination of its salt and one or more pharmaceutical carrier.
Nicotinoyl amino acids of the present invention is normally taken with the form of pharmaceutical composition, can oral or non-oral administration, the perhaps compound to form with pharmaceutically acceptable carrier, vehicle and other additive, for example oral or non-oral administration of tablet, sustained release preparation, capsule, injection, solution or the like safety.When oral administration, composition can be mixed with tablet, sugar-coat agent or capsule.For the preparation combination of oral medication can adopt lactose or starch to do carrier, gelatin, Xylo-Mucine, methylcellulose gum, polyvinylpyrrolidone etc. are suitable wedding agents or become an agent.Can select starch or Microcrystalline Cellulose for use as disintegrating agent, often with talcum powder, santocedl, stearin, calcium stearate or magnesium etc. are as suitable antiadhesives and lubricant.
In another aspect of this invention, provide a kind of nicotinoyl amino acids or its salt in preparation to the application aspect the tumor radiotherapy hypersitization medicine.Wherein said tumour comprises lung cancer, liver cancer, mammary cancer, cervical cancer, lymphatic cancer or nasopharyngeal carcinoma.
The discovery 01. nicotinoyl Padil that the inventor is surprised under study for action; 02 nicotinoyl alanine; 03 nicotinoyl aspartic acid; 04 nicotinoyl-2-aminobutyric acid; 05 nicotinoyl aminobutyric acid; 06 nicotinoyl aminovaleric acid; 07 nicotinoyl iminodiethanoic acid; 08 nicotinoyl imino-diacetic propionic acid; 09 nicotinoyl imino-diacetic butyric acid or its pharmacy acceptable salt (mainly being sodium salt, sylvite) have sensitization to the radiotherapy of lung cancer, liver cancer, mammary cancer, cervical cancer, lymphatic cancer or nasopharyngeal carcinoma.
Nicotinuric acid, nicotinoyl aminobutyric acid, nicotinoyl aminovaleric acid, nicotinoyl aspartic acid, nicotinoyl 2-aminobutyric acid.These compounds have the effect of tuberculosis and antifatigue aspect, and existing the discovery also produces effect as the tumor radiotherapy enhanced sensitivity.For example the radiotherapy to lung cancer, liver cancer, mammary cancer, cervical cancer, lymphatic cancer or nasopharyngeal carcinoma has all demonstrated sensitization.
Its mode of action of nicotinoyl amino acids of the present invention: when cooperating radiotherapy, take the radiation sensitivity that the nicotinoyl amino acids can significantly strengthen cancer cells simultaneously, thereby can reduce the irradiation total dose, improve the radiotherapeutic effect of tumour, reduce the toxic side effects that radiotherapy causes, provide the effect experiment data of 01-07 compound below.
1 materials and methods
1.1 the model of animal
Select ICR mouse (available from Tumour Inst., Chinese Medical Academy) for use, mouse 7-8 in age week, body weight 18-20g, male and female half and half.The knurl strain is that transplantation experiments tumour (drawing the tumour institute from the Chinese Academy of Medical Sciences) is taken out the knurl body according to a conventional method in the tumor-bearing mice body, makes tumor cell suspension, by cell count 1 * 10 6It is outer subcutaneous to be inoculated in the right leg of mouse, and every mouse 0.2ml treats tumor growth to 250 ± 50mm 3The time begin group experiment, generally transplanted the back 7-10 days.
1.2 medicine: animals administer dosage: be 1/4th of medium lethal dose, drug level 50mg-100mg/ml is in pre-irradiation 2-3 hour one time intraperitoneal administration.
1.3 illuminating method: irradiation is adopted 60Co gamma-rays vertical irradiation; dose rate 81.79cGy/min, 4 mouse of a dose point once irradiating are put into special synthetic glass box internal fixing with mouse; only shining the lotus knurl retreats; other position is protected with lead, adopts Denekampq single fraction irradiation method, divides 10; 15; 20Gy, 3 dose points, single fraction irradiation respectively.
1.4 laboratory animal grouping: tumor-bearing mice is divided into 4 groups at random, and wherein simple radiation group and medicine add radiation and organize each minute 3 radiation dose groups, every group of 6 mouse.
＜1〉blank group: do not add any processing.＜2〉simple medication group: intraperitoneal injection of drugs.＜3〉simple radiation group: divide 3 dose point irradiations.＜4〉medicine adds the irradiation group: divide 3 dose point irradiations, illuminating method and dosage are identical with simple radiation group, and medication and consumption are with simple administration group.
The result:
2.1 tumor growth curve: every other day measure the volume that the knurl body increases in the experiment, till gross tumor volume rises to 4 times of volume when beginning to test, according to steel gross tumor volume calculation formula: volume=length * wide 2/ 2 calculate, and calculate and the drafting tumor growth curve, respectively organize the growth of tumor situation, respectively organize tumor average volume differences not remarkable (P＞0.05) before the treatment
2.2 tumor growth delay (TGD) and radiation sensitization are than (SER); Gross tumor volume reaches the fate of when irradiation 4 times of volumes, and the fate of 4 times of volumes is tumor growth delay when deducting control group and reaching experiment, and the dose,equivalent of simple radiation group adds the dose,equivalent of radiation group divided by medication, for radiation sensitization than (SER).
Each compound of table 1. is to the radiosensitizing effect of six kinds of cancers
Compound number Lung cancer Lewis SER Liver cancer H22 SER Mammary cancer MCF-7 SER Cervical cancer Hela SER Lymphatic cancer U937 SER Nasopharyngeal carcinoma KB SER
01 1.4 1.36 1.5 1.4 1.45 1.5
02 1.3 1.4 1.51 1.43 1.47 1.55
03 1.45 1.3 1.54 1.45 1.61 1.56
04 1.5 1.3 1.58 1.61 1.47 1.52
05 1.6 1.3 1.67 1.61 1.54 1.65
06 1.43 1.47 1.56 1.62 1.54 1.45
07 1.3 1.3 1.55 1.61 1.58 1.52
(seven compounds do not have radiosensitizing effect SER between 1.0-1.1 to normal artificial skin and small intestine crypts.)
Embodiment
The present invention is described further below in conjunction with embodiment, embodiment only is indicative, mean that never it limits the scope of the invention by any way, compound of the present invention is through high performance liquid chromatography (HPLC), thin-layer chromatography (TLC), fusing point (m.p.) detects, can adopt subsequently nucleus magnetic resonance ( 1HNMR/ 13CNMR) etc. further prove conclusively its structure.
In the experiment needed intermediate can buy from market or can be easily method by top narration or other document known method make.Nicotinoyl nitrine of the present invention synthetic referring to Sidey W.Fox, Henry field, Jr.The synthesis of nicotinuricacid.J.Biol.chem 147:651 (1943).
Example 1
Nicotinic acid hydrazide 18.7 (130mM) is dissolved among 13% the hydrochloric acid soln 122.2ml, and low temperature drips NaNO down 218.2g (260mM) at the solution of water 45ml, drip and finish, continue reaction 1.5 hours, reaction mixture Na 2CO 3Transfer PH to 7, with ether extraction (100ml * 4), organic layer washing, CaCl 2Drying is removed and is desolvated, and gets the 16.6g product, (86%).，
Example 2
Synthesizing of N-nicotinoyl iminodiethanoic acid
Nicotinoyl nitrine 2.3g (15.5mM) adds in the solution of 1N sodium hydroxide 16ml of iminodiethanoic acid 2.1g (15.5mM), stirred 12 hours, be neutralized to PH to 3-4 with hydrochloric acid then, the rotation concentration of reaction solution is separated out 202-203 ℃ of white crystals 80% recrystallizing methanol mp to small volume (PH 3-4).
1HNMR(DMSO-d6)， δ(ppm)4.10(d，4H，-CH2-，-CH2-)，7.48((dd，1H，H5)，7.73(dd，1H，H4)，8.50(dd，1H，H6)，8.66(q，1H，H2)。
Example 3
2-nicotinoyl aminobutyric acid
The gradation of nicotinoyl nitrine 3.1g (21mM) powder adds to DL-2-aminobutyric acid 2.16g (21mM) in the solution of 1NNaOH 21ml, finish, continue to stir 12 hours, rotation concentrate dope, drip 2NHCl and transfer PH to 4, separate out 212-214 ℃ of white precipitate 3.6g (82%) mp, ethyl alcohol recrystallization.
1HNMR(DMSO-d6) δppm0.968(t，3H，CH3)，1.810(m，2H，CH2)，4.317(m，1H，-CH-)，7.526(dd，1H，C53)，8.229(m，1H，C42)，8.727(m，1H，H6’)，8.821(d，1H，C21)，9.039(d，1H，NH)12.666(S，1H，OH)，Anal C 11H 12N 2O 3C，H，N。
Example 4 nicotinoyl Padils: the similar example 3 of preparation method, the nicotinoyl nitrine: Padil=1: 1.5, obtain white crystal, mp is 250-253 ℃.
Example 5 nicotinoyl alanines: the similar example 3 of preparation method, the nicotinoyl nitrine: Padil=1: 1.5, obtain white crystal, mp is 143-145 ℃.
Example 6 nicotinoyl aspartic acids: the similar example 2 of preparation method, L-aspartic acid 1.8 grams (0.0135mol), add 15ml1N NaOH stirring and dissolving, gradation adds nicotinoyl nitrine 2g (0.0135mol), and PH is controlled at 9-9.5, behind the reaction 8h, transfer PH to 4-4.5 with hydrochloric acid, add the MeOH precipitation, filter, get white crystal, mp is 194-195 ℃.
Example 7: nicotinoyl aminobutyric acid: the similar example 2 of preparation method, nicotinoyl nitrine 5.9g (0.04mol) adds 0.01N NaOH 113ml, stirring and dissolving adds 6g (0.058M) aminobutyric acid, continues to stir, the adularescent precipitation is separated out, transfer PH to 8-9 with NaOH, be concentrated to small volume, transfer PH to 4 with HCl, there is precipitation to separate out, filter, get white crystals, mp is 210-211 ℃.
Example 8 amido valeric acids: the similar example 3 of preparation method, the nicotinoyl nitrine: aminovaleric acid=1: 3,40 ℃ of temperature, get white crystal mp201-202 ℃ at 12 hours time.
Example 9 nicotinoyl imino-diacetic propionic acid: the similar example 2 of preparation method, the nicotinoyl nitrine: amino dipropionic acid=1: 3.5, white crystal, mp is 210-213 ℃.
Example 10 nicotinoyl imino-diacetic butyric acid: the similar example 2 of preparation method, the nicotinoyl nitrine: imino-diacetic butyric acid=1: 4.2, get white crystals, mp is 230-231 ℃.
Example 11 nicotinoyl iminodiacetic acid sodium salt: with NaHCO 321.4g (0.2M) be dissolved in the 80ml water, add the amino oxalic acid 23.8g (0.1mol) of 2-nicotinoyl, treat complete molten after, boil off water, white crystal.Example 12 nicotinoyl-2-aminobutyric acid sylvite: with KHCO 313.9g (0.1M) be dissolved in the 60ml water, add nicotinoyl aminobutyric acid 20.8 grams (0.1M), treat complete molten after, boil off water, obtain white crystal.
Embodiment 13 every tablet preparation that contain the 10mg activeconstituents are as follows:
Compound (02) 100mg, Microcrystalline Cellulose 35mg, starch 45mg, polyvinylpyrrolidone 4mg, Magnesium Stearate 4.0, talcum powder 1mg.Preparation method: with activeconstituents, starch and Mierocrystalline cellulose sieve, and thorough mixing, polyvinylpyrrolidonesolution solution is mixed with above-mentioned powder, sieve, make wet granular in 50-60 ℃ of drying, with the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
Embodiment 14
The compound 10g of preparation adds 40g (lactose-microcrystalline cellulose 5: 1), Magnesium Stearate 1%, with 70% alcohol granulation, compressing tablet among the embodiment 8.
Embodiment 15
The compound 10g of preparation adds dextrin 10g, lactose 30g with 60% alcohol granulation, drying, encapsulated among the embodiment 12, makes 1000 seed lac wafers.
After the preferred embodiment that describes in detail, being familiar with this technology personage can be well understood to, can carry out various variations and modification not breaking away under above-mentioned claim and the spirit, all foundations technical spirit of the present invention all belongs to the scope of technical solution of the present invention to any simple modification, equivalent variations and modification that above embodiment did.And the embodiment that the present invention also is not subject in the specification sheets to be given an actual example.

Claims (9)

1, the compound or its pharmacy acceptable salt that have the following formula structure
Figure A2007100571690002C1
Wherein, R is-NHR 1COOH;-N (R 2COOH) 2-NH (R 3COOH) 2-NH-R 4(R 5)-COOH;
R 1Be C1-C6 straight or branched alkyl;
R 2Be the C1-C4 straight chained alkyl;
R 3-5Be the C1-C3 straight chained alkyl.
2, the described compound of claim 1, wherein, R 1Be C1-C4 straight or branched alkyl; R 2Be the C1-C4 straight chained alkyl; R 3-5Be the C1-C3 straight chained alkyl.
3, compound as claimed in claim 1, it is selected from:
01. nicotinoyl Padil;
02 nicotinoyl alanine;
03 nicotinoyl aspartic acid;
04 nicotinoyl-2-aminobutyric acid;
05 nicotinoyl aminobutyric acid;
06 nicotinoyl aminovaleric acid;
07 nicotinoyl iminodiethanoic acid;
08 nicotinoyl imino-diacetic propionic acid;
09 nicotinoyl imino-diacetic butyric acid or its pharmacy acceptable salt.
4, a kind of method for preparing the described compound of claim 1-3 is characterized in that in polar solvent, amino acid is mixed with the nicotinoyl nitrine carry out acylation reaction, 0-50 ℃ of reaction 8-14 hour, makes the nicotinoyl amino acids; The ratio of weight and number of amino acid wherein and nicotinoyl nitrine is 1-5: 1.
5, method as claimed in claim 4, polar solvent wherein are water, ethanol, methyl alcohol or Virahol.
6, a kind of pharmaceutical composition is characterized in that comprising any one compound or its salt and pharmaceutically acceptable one or more pharmaceutical carriers of claim 1-3.
7, claim 1-3 any one the nicotinoyl amino acids or its salt in preparation to the application aspect the tumor radiotherapy hypersitization medicine.
8, nicotinoyl Padil, nicotinoyl alanine, nicotinoyl aminobutyric acid, nicotinoyl aminovaleric acid, nicotinoyl aspartic acid, nicotinoyl 2-aminobutyric acid, nicotinoyl iminodiethanoic acid, nicotinoyl imino-diacetic propionic acid or the nicotinoyl imino-diacetic butyric acid application in preparation treatment tumor radiotherapy hypersitization medicine.
9, as claim 7 or 8 described application, wherein said tumour comprises lung cancer, liver cancer, mammary cancer, cervical cancer, lymphatic cancer or nasopharyngeal carcinoma.
CNA2007100571690A 2007-04-20 2007-04-20 Method for synthesizing nicotinyl amino acids and sensitizing effect thereof to tumor radiotherapy Pending CN101289421A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107362362A (en) * 2017-07-20 2017-11-21 复旦大学 Application of the SIRT1 inhibitor in radioactive intestines problem is prevented and treated
CN111603560A (en) * 2020-06-22 2020-09-01 泉州台商投资区秋鑫茶业有限公司 Application of tea gamma-aminobutyric acid in tumor radiotherapy

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107362362A (en) * 2017-07-20 2017-11-21 复旦大学 Application of the SIRT1 inhibitor in radioactive intestines problem is prevented and treated
CN107362362B (en) * 2017-07-20 2019-01-01 复旦大学 SIRT1 inhibitor is preventing and treating the application in radioactive intestines problem
CN111603560A (en) * 2020-06-22 2020-09-01 泉州台商投资区秋鑫茶业有限公司 Application of tea gamma-aminobutyric acid in tumor radiotherapy

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