CN1939912A - Production of N-[2-(3-phenyl2-phenallyamido) propionyl-timonacic and its derivative - Google Patents
Production of N-[2-(3-phenyl2-phenallyamido) propionyl-timonacic and its derivative Download PDFInfo
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- CN1939912A CN1939912A CN 200510106097 CN200510106097A CN1939912A CN 1939912 A CN1939912 A CN 1939912A CN 200510106097 CN200510106097 CN 200510106097 CN 200510106097 A CN200510106097 A CN 200510106097A CN 1939912 A CN1939912 A CN 1939912A
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Abstract
Production of N-(2-(3-phenyl-2-acrylamide)propionyl)-timonacic and its derivative is carried out by retaining unsaturated double-key in active compound structure, designing rational rout, replacing praline with timonacic and its derivative to obtain the final product. It can be used to prepare low-toxicity and efficient ACEI.
Description
Denomination of invention
N-[2-(3-phenyl-2-acrylamido) propionyl]-thiazolidinecarboxylic acid and derivative preparation method thereof
Technical field
Organic chemistry
Background technology
ACEI (Angiotensin Converting Enzyme Inhibitor) is an angiotensin converting enzyme inhibitor, it is a new milestone on the cardiovascular agent history, its maximum work usefulness is exactly the effective treatment to high blood pressure disease, angiotensin-converting enzyme ACE (Angiotensin Converting Enzyme) is a kind of film fixed metalloprotease, it contains 1306 amino acid, and result of study shows and contains a Zn in the active centre
2+, protonated arginine and hydrophobic cavity
[1]On physiological action, it is the key enzyme of the renin-angiotensin system of blood pressure regulation in the body
[2]The Angiotensin source is a kind of glycoprotein, after the feritin effect, it is the polypeptide of a non-activity that the Angiotensin source cracking of being made up of 453 amino acid discharges 10 amino acid whose polypeptide angiotensin Is (AngI), but menses angiotensin conversion enzyme enzymolysis, obtain the Angiotensin II (AngII) of octapeptide, AngII is the strongest known active substance that boosts.
In addition, ACE has the function of degraded inactivation bradykinin again, the effect that bradykinin has vasodilation, diuresis, brings high blood pressure down, and ACE is present in the film surface of vascular endothelial cell in a large number, endogenous Ang I and bradykinin all can be transformed by it in the blood, cause increased blood pressure from two aspect effects.People are according to this constructional feature design of ACE and synthesized many angiotensin converting enzyme inhibitors
Through 20 years of researches and clinical experiment, kind of ACEI kind new medicine listing surplus in the of existing 30 at present, the ACEI of clinical application is according to different with ACE active centre binding site in the body, can be divided three classes: the first kind is the ACEI that contains sulfydryl, as captopril (captopril), zofenopril (zofenopril), alacepril (alacepril); Second class is carboxylic ACEI, as enalapril (enalapril), lisinopril (lidinopril), uncommon Puli (cilazapril), Ramipril (ramipril), benazepril (benazepril), the quinapril (quinapril) of drawing; The 3rd class is the ACEI that contains phosphoryl, as fosinopril (fosinpril).As shown in the figure:
The dummy model in figure ACE active function site: hydrophobic pocket (a) adds binding site (b)
They in bioavailability, plasma half-life, excretion pathway, distribution, and each is different the aspects such as affine body of tissue bond ACE.Although ACEI with oral effectively, antihypertensive effect is good and extensive concern lasting, advantage has been subjected to international and domestic the world of medicine such as therapeutic domain is wide, side effect is little, but also is no lack of negative report, after some patient takes, the untoward reaction of some medicines relevant with compound structure has appearred, as dry cough, asthma and bone marrow depression, vasodilation, itch and Oncocytosis etc.
[3-5], caused that people more and more pay close attention to.How seeking and synthesizing outstanding ACEI is a very active field studying cardiovascular disorder.
Recent studies show that
[6-8], with α, the beta-unsaturated acyl aminated compounds has been obtained initial achievements as a class potential ACE inhibitor, and this compounds so overcome the toxic side effect of first kind compound, estimates to have prospect preferably owing to do not contain sulfydryl.Your addition of Mike can partly take place with the nucleophilic of active end among the ACE in α, beta-unsaturated acyl amine, and the carboxyl of the L-glutamic acid nucleophilic reagent known to us just.If α, the N end of beta-unsaturated acyl amine combines with ACE as hydrogen bond receptor, the carbonyl of this acid amides will be in conjunction with the Zn ion part (as figure below) of this enzyme so, the α of this acid amides then, β-unsaturated double-bond can be changed the carboxyl generation reversal of the Michael addition of the Glu-127 (L-glutamic acid) of enzyme with this by the catalysis carboxylation.Finally cause Zinc metallopeptidase Zace1 by irreversible inhibition.Thereby reach the effect that brings high blood pressure down.
A series of α that are synthesized in these researchs have had been found that several experimentation on animals effects preferably that obtained, but have not entered clinical stage as yet in beta-unsaturated acyl amine and the derivative thereof.N-[2-(3-phenyl-2-acrylamido) propionyl wherein] IC of proline(Pro)
50(mM) be 0.23, effect is better.Structure such as figure below (left side):
The interior acyl group of N-[2-(3-phenyl-2-acrylamido)] proline(Pro) N-[2-(3-phenyl-2-acrylamido) propionyl] thiazolidinecarboxylic acid and derivative thereof
The present invention is based on above-mentioned N-[2-(3-phenyl-2-acrylamido) propionyl] proline(Pro), it is changed structure modify, we keep unsaturated double-bond part in its structure, design synthetic route, novel ACEI efficient in the hope of obtaining, low toxicity.We partly are replaced by thiazolidinecarboxylic acid and derivative thereof with its proline(Pro) in synthetic route; obtain a series of N-[2-(3-phenyl-2-acrylamido) propionyl]-thiazolidinecarboxylic acid and derivative thereof, structure is as above schemed (right side), and this compounds also belongs to α; the beta-unsaturated acyl aminated compounds
On pharmacology, thiazolidinecarboxylic acid is proved to be has antitumor action
[9-18], the mechanism of action is that it is decomposed into halfcystine and formaldehyde in vivo.Halfcystine is woven with certain avidity as carrier to tumor group, and the aldehyde part then can act on the nucleic acid or the proteinic nucleophilic part of oncocyte.
On structure, nearest studies show that
[19], thiazolidinecarboxylic acid has bigger electric density than proline(Pro), and this is because the thiazolidine carboxylic acid is a kind of proline(Pro) of replacement, and CH
2After being replaced by S, the electric density of carboxylic acids on the electron rich of the last existence of S can be strengthened 4, make its can with more stable the combining of hydrophobic pocket, combine with protonated arginine position among the ACE and to have obtained reinforcement.Discover that it is thiazolidinecarboxylic acid and derivative thereof that the proline(Pro) in the enalapril structure among the second class ACEI is partly changed structure, has obtained The pharmacological results preferably.
Summary of the invention
The compound that relates in the document has had The pharmacological results preferably, the present invention changes structure on this basis and modifies, according to the original new drug design concept, we consider from 3 aspects: the first, keep the traditional primary activity site that has listing ACEI now; The second, manage to shelter existing ACEI toxic side effect site; The 4th, break through existing listing ACEI mechanism of action, design the novel ACE I compound of brand-new mechanism of action, the synthetic route of the present invention's design, its target are to obtain novel ACE I efficient, low toxicity.
We adopt present polypeptide synthetic general method on the synthetic route layout strategy; promptly with being formed dipeptides by the L-Ala and the thiazolidinecarboxylic acid condensation of Boc-group and ester group protection respectively; then will be behind the deprotection styracin of acidylate receive the N end of dipeptides, promptly obtain our target compound.
Description of drawings
Wherein R is:
Embodiment
Experimental procedure is as follows:
Synthesizing of thiazolidinecarboxylic acid and derivative thereof
[17-18]
With L-cysteine hydrochloride monohydrate 5g, (0.028mol) (M=175.64), K
AC3.5g 95% ethanol 15ml and water 25ml mix, and add 36% formaldehyde 3ml (0.029mol), stir 3h under the room temperature, crystal, suction filtration are separated out in the frozen water cooling, washing with alcohol, the dry crude product that gets is with crude product water 25ml heating for dissolving, filtered while hot adds 95% ethanol 25ml in the filtrate, be cooled to 3 ℃, suction filtration, washing with alcohol with 95% three times, dry white crystal 3.2g, the yield 84.4% of getting.
All the other derivative synthesizing process are the same.
Synthesizing of the hydrochloride of thiazolidine acid esters
[21]
2g (0.015mol) L-Thioproline is suspended in the 16mL dehydrated alcohol, feeds the exsiccant hydrogen chloride gas under the room temperature to saturated (stirring the dissolving of accelerating the L-Thioproline).Placement is spent the night, and is evaporated to dried.To precipitate and use a small amount of anhydrous alcohol solution, twice of evaporated under reduced pressure and repetitive operation to be eliminating unnecessary hydrogenchloride again, otherwise product is clamminess easily.To precipitate at last and be dissolved in again in a small amount of warm dehydrated alcohol, add anhydrous diethyl ether till no longer separating out crystallization.Place a few hours in refrigerator after, filter, collect crystal, with the washing of ethanol-ether (1: 2) mixed solution, drying is weighed, compound.
The hydrochloride of remaining thiazolidinecarboxylic acid synthetic the same.
The generation of peptide bond
The Boc-L-L-Ala of 2.93g (0.0155mol) is dissolved among the THF of 30ml the Thioproline carbethoxy hydrochloride of HoBt, the 3.13g (0.0155mol) of adding 4.18g (0.031mol) and the N-Ethylmorphine quinoline of 1.99ml (0.0155mol).The ice-cold THF solution that adds the 5ml of 3.37g (0.0163mol) DCC under 0 ℃ of cooling and stirring, 0 ℃ is stirred 1h, room temperature restir 1h, TLC monitoring reaction process.Elimination DCU, filtrate decompression is concentrated into dried.Residue is dissolved in the ethyl acetate, uses saturated NaHCO successively
3, the citric acid of 2N, NaHCO
3Be washed till neutrality with saturated NaCl.Add anhydrous Na SO
4Drying, concentrating under reduced pressure desolvates.Get product.
All the other derivative synthesizing process are the same.
Removing of BOC-protecting group
To join in the HCl-EtOAc solution of 15ml by the compound 2.1g (0.005mol) that the reaction of last step generates.Stir, TLC monitoring reaction process, treat that the BOC reaction finishes after, be spin-dried in the 35-40 ℃ of water-bath, EtOAc exchange 3 times, vacuum-drying promptly gets compound.
The preparation of cinnamyl chloride
The SOCl that heavily steamed
21.79g (30mmol) join in the styracin of 20mmol, stir 2h, remaining SOCl down at 80 ℃
2Revolve to steam and remove.
The preparation of target compound
In ice-water bath, dipeptides is dissolved among the NaOH6.5ml of 1mol/L, the NaOH and the freshly prepd cinnamyl chloride (6.5mmol) that add 3.5ml (2mol/L) under the room temperature vigorous stirring, reaction 3h, the reaction product ether extraction, water layer is acidified to PH 1-2 with concentrated hydrochloric acid, ethyl acetate extraction, washing, anhydrous MgSO
4Drying is filtered, the pressure reducing and steaming solvent, and residuum gets product with ether-chloroform recrystallization.
Contriver's situation
Dai Bin: the man, give birth in October, 1969, professor, doctor, chemical institute of Shihezi Univ
Wang Dong: man, in June, 1972, experimentalist, Master degree candidate, chemical institute of Shihezi Univ
Liu Zhiyong: the man, give birth in October, 1969, associate professor, doctor, chemical institute of Shihezi Univ
Gu Chengzhi: the man, give birth in March, 1975, lecturer, master, chemical institute of Shihezi Univ
Zhong Lingli: the woman, give birth to October nineteen eighty-two, Master degree candidate, chemical institute of Shihezi Univ
Ma Xiaowei: woman, in October, 1979, assiatant, Master degree candidate, chemical institute of Shihezi Univ
Li Wenjuan: woman, in November, 1980, assiatant, Master degree candidate, chemical institute of Shihezi Univ
Reference
[1] Shen Yao, Yan Yuanqing. the clinical pharmacodynamics of non-sulfydryl class ACEI and pharmacokinetics [J]. Yun county sun medical college of Tongji Medical Univ journal, 1994,13 (1): 47.
[2] Zheng Hu. pharmaceutical chemistry [M]. Beijing: People's Health Publisher, 1998.
[3] Lei Suimin, Zhang Shuyi .ACEI clinical application recent developments [J]. clinical assembling, 1998,13 (9): 385.
[4] Fu Wen brocade .ACEI causes dry cough 11 examples [J]. Shaanxi medical journal, 1994,5 (23): 5.
[5] modern Application of Han Yong rosy clouds .ACEI and precaution [J]. seek medical advice and medicine 2003,10 (9): 58-60.
[6]Ghosh?S.S.，Wu?Y.Q.，Mobashery?S.，J.Biol.Chem.226(1991)8759-8764.
[7]Ghosh?S.S.，Dakoji?S.，Tanaka?Y.，Mobashery?S.，Bioorg.Med.Chem.4(1996)1487-1492.
[8]Hea?Young?Park?Choo，Kyung?Hee?PeaK，Jongsei?Park.，Eur.J.Med.Chem.35(2000)643-648.
[9]Brugarolas?A.et?al：Lancet?1980，1(8159)：68
[10] Li Yixin. external pharmacy [J] .1981,2 (1): 22.
[11] tribute heavily fortified point. new drug and clinical [J] .1984,3:192.
[12] Feng accuses the gate of a lane. Jiangxi Medical College's journal [J] .1984, (2): 83.
[13] yellow happy Hong. tumour [J] .1984,2:80.
[14]Paul?B?et?al.J?Med?chem[J].1976，19：1002.
[15]Tillian?H?W?et?al.E?UR?j?cancer[J].1976，12：99.
[16] day disclosure special permission 1980,167220:(CA 1981,94:1325830).
[17] Zhang Yanliang etc. the synthetic and anti-tumor activity [J] of thiazolidine sugar derivatives. medicine industry, 1988,19 (4): 152.
[18] Liu Jiyun etc. the synthetic and Antitumor Effects [J] of thiazolidinecarboxylic acid compounds. medicine industry, 1988,19 (5): 203.
[19] tribute Xiao Wei. the design of novel thiazole alkane-4-carboxylic-acid angiotensin-convertion enzyme inhibitor and synthetic [D]. Jinan: Shandong University, 2001.
[20] Huang Weide, Chen Changqing. " polypeptide is synthetic " Beijing: Science Press, 1981.
Claims (3)
1. mentality of designing
The compound that relates in the document has had The pharmacological results preferably, and the present invention changes structure on this basis and modifies, and according to the original new drug design concept, has designed synthetic route, and its target is to obtain novel ACE I efficient, low toxicity.
(2.N-[2-3-phenyl-2-acrylamido) propionyl]-synthetic route of thiazolidinecarboxylic acid and derivative thereof
The synthetic route chart of thiazolidinecarboxylic acid and derivative thereof is as follows:
The synthetic route chart of target compound is as follows:
3. target compound
III is target compound: wherein the R in substituent R and thiazolidinecarboxylic acid and derivative thereof synthetic is identical.
N-[2-(3-phenyl-2-acrylamido) propionyl]-thiazolidinecarboxylic acid and derivative thereof
4. target compound synthetic method:
Synthesizing of thiazolidinecarboxylic acid and derivative thereof
With L-cysteine hydrochloride monohydrate 5g, (0.028mol) (M=175.64), K
AC3.5g 95% ethanol 15ml and water 25ml mix, and add 36% formaldehyde 3ml (0.029mol), stir 3h under the room temperature, crystal, suction filtration are separated out in the frozen water cooling, washing with alcohol, the dry crude product that gets is with crude product water 25ml heating for dissolving, filtered while hot adds 95% ethanol 25ml in the filtrate, be cooled to 3 ℃, suction filtration, washing with alcohol with 95% three times, dry white crystal 3.2g, the yield 84.4% of getting.
All the other derivative synthesizing process are the same.
Synthesizing of the hydrochloride of thiazolidine acid esters
2g (0.015mol) L-Thioproline is suspended in the 16mL dehydrated alcohol, feeds the exsiccant hydrogen chloride gas under the room temperature to saturated (stirring the dissolving of accelerating the L-Thioproline).Placement is spent the night, and is evaporated to dried.To precipitate and use a small amount of anhydrous alcohol solution, twice of evaporated under reduced pressure and repetitive operation to be eliminating unnecessary hydrogenchloride again, otherwise product is clamminess easily.To precipitate at last and be dissolved in again in a small amount of warm dehydrated alcohol, add anhydrous diethyl ether till no longer separating out crystallization.Place a few hours in refrigerator after, filter, collect crystal, with the washing of alcohol-ether (1: 2) mixed solution, drying is weighed, compound.
The hydrochloride of remaining thiazolidinecarboxylic acid synthetic the same.
The generation of peptide bond
The Boc-L-L-Ala of 2.93g (0.0155mol) is dissolved among the THF of 30ml the Thioproline carbethoxy hydrochloride of HoBt, the 3.13g (0.0155mol) of adding 4.18g (0.031mol) and the N-Ethylmorphine quinoline of 1.99ml (0.0155mol).The ice-cold THF solution that adds the 5ml of 3.37g (0.0163mol) DCC under 0 ℃ of cooling and stirring, 0 ℃ is stirred 1h, room temperature restir 1h, TLC monitoring reaction process.Elimination DCU, filtrate decompression is concentrated into dried.Residue is dissolved in the ethyl acetate, uses saturated NaHCO successively
3, the citric acid of 2N, NaHCO
3Be washed till neutrality with saturated NaCl.Add anhydrous Na SO
4Drying, concentrating under reduced pressure desolvates.Get product.
All the other derivative synthesizing process are the same.
Removing of BOC-protecting group
To join in the HCl-EtOAc solution of 15ml by the compound 2.1g (0.005mol) that the reaction of last step generates.Stir, TLC monitoring reaction process, treat that the BOC reaction finishes after, be spin-dried in the 35-40 ℃ of water-bath, EtOAc exchange 3 times, vacuum-drying promptly gets compound.
The preparation of cinnamyl chloride
The SOCl that heavily steamed
21.79g (30mmol) join in the styracin of 20mmol, stir 2h, remaining SOCl down at 80 ℃
2Revolve to steam and remove.
The preparation of target compound
In ice-water bath, dipeptides is dissolved among the NaOH6.5ml of 1mol/L, the NaOH and the freshly prepd cinnamyl chloride (6.5mmol) that add 3.5ml (2mol/L) under the room temperature vigorous stirring, reaction 3h, the reaction product ether extraction, water layer is acidified to PH 1-2 with concentrated hydrochloric acid, ethyl acetate extraction, washing, anhydrous MgSO
4Drying is filtered, and pressure reducing and steaming solvent, residuum E-C recrystallization gets product.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011112535A3 (en) * | 2010-03-10 | 2011-12-22 | Promentis Pharmaceuticals, Inc. | Propionic acids, propionic acid esters, and related compounds |
| CN102603666A (en) * | 2012-02-28 | 2012-07-25 | 石河子大学 | Cinnamoyl tauryl timonacic compound and application thereof |
| WO2012176621A1 (en) * | 2011-06-24 | 2012-12-27 | 株式会社ダイセル | Method for producing unsaturated carboxylic acid amide composition |
| WO2016082786A1 (en) * | 2014-11-27 | 2016-06-02 | 西北大学 | Tripeptide compound, preparation method therefor, and application thereof |
| JP2016121130A (en) * | 2011-02-09 | 2016-07-07 | プサン ナショナル ユニヴァーシティ インダストリー ユニヴァーシティＰｕｓａｎ Ｎａｔｉｏｎａｌ Ｕｎｉｖｅｒｓｉｔｙ Ｉｎｄｕｓｔｒｙ−Ｕｎｉｖｅｒｓｉｔｙ | Novel compound having skin-whitening, anti-oxidizing and ppar activities and medical use thereof |
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- 2005-10-01 CN CN 200510106097 patent/CN1939912A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011112535A3 (en) * | 2010-03-10 | 2011-12-22 | Promentis Pharmaceuticals, Inc. | Propionic acids, propionic acid esters, and related compounds |
| JP2016121130A (en) * | 2011-02-09 | 2016-07-07 | プサン ナショナル ユニヴァーシティ インダストリー ユニヴァーシティＰｕｓａｎ Ｎａｔｉｏｎａｌ Ｕｎｉｖｅｒｓｉｔｙ Ｉｎｄｕｓｔｒｙ−Ｕｎｉｖｅｒｓｉｔｙ | Novel compound having skin-whitening, anti-oxidizing and ppar activities and medical use thereof |
| WO2012176621A1 (en) * | 2011-06-24 | 2012-12-27 | 株式会社ダイセル | Method for producing unsaturated carboxylic acid amide composition |
| JP2013006795A (en) * | 2011-06-24 | 2013-01-10 | Daicel Corp | Method for producing unsaturated carboxylic amide composition |
| CN102603666A (en) * | 2012-02-28 | 2012-07-25 | 石河子大学 | Cinnamoyl tauryl timonacic compound and application thereof |
| WO2016082786A1 (en) * | 2014-11-27 | 2016-06-02 | 西北大学 | Tripeptide compound, preparation method therefor, and application thereof |
| CN105693817A (en) * | 2014-11-27 | 2016-06-22 | 西北大学 | Tripeptide compound and preparation method and application thereof |
| US20170267718A1 (en) * | 2014-11-27 | 2017-09-21 | Northwest University | Tripeptide compound, preparation method therefor, and application thereof |
| CN105693817B (en) * | 2014-11-27 | 2020-06-05 | 西北大学 | Tripeptide compound and preparation method and application thereof |
| US11358985B2 (en) * | 2014-11-27 | 2022-06-14 | Northwest University | Tripeptide compound, preparation method therefor, and application thereof |
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