CN101270099A - Method for preparing N-[2-(1-ethoxycarbonyl-3-phenylpropylamino)-tauryl]-thiazolidinecarboxylic acid and its derivant - Google Patents

Abstract

According to the conception of a novel drug design, the present invention provides improved decoration based on the existing ACEI and relates to a design comprising the following two types of conception: first, the toxic side-effect points of the existing ACEI are avoided to the greatest extent; secondly, the effects of the ACEI are improved to the greatest extent. Thus the present invention provides a novel ACEI compound. Based on the basic structure of enalapril, the present invention provides a synthetic route for improving decoration. The structure of propanamine-sulfonyl is changed into cattle sulphonyl; the praline is changed into timonacic acid and derivatives thereof, so as to prepare a series of compounds, namely, N-[2-(1-ethoxycarbonyl-3-phenylalanine)-cattle-sulfonyl]-timonacic acid and derivatives thereof. The drugs are screened to prepare novel high-efficiency and low-toxicity ACEI.

Description

N-[2-(1-ethoxy acyl group-3-phenylpropyl alcohol amino)-tauryl]-thiazolidinecarboxylic acid and derivative preparation method thereof

Technical field

Organic chemistry

Background technology

(Angiotensin Converting Enzyme Inhibitor, (Renin-Angiotensin System RAS), suppresses hypertensin conversion enzyme activity to angiotensin-convertion enzyme inhibitor ACEI) mainly to act on renin-angiotensin system.Renin-angiotensin system plays an important role in the process of blood pressure regulation.Angiotensin-converting enzyme is a kind of film fixed metalloprotease, and it contains 1306 amino acid, and result of study shows and contains a Zn in the active centre ²⁺, protonated arginine and hydrophobic cavity.On physiological action, it is the key enzyme of the renin-angiotensin system of blood pressure regulation in the body.The Angiotensin source is a kind of glycoprotein, after the feritin effect, the Angiotensin source cracking of being made up of 453 amino acid discharges the polypeptide angiotensin I (AngI) of 10 amino acid whose non-activities, but menses angiotensin conversion enzyme enzymolysis, obtain the Angiotensin II (AngII) of octapeptide, and Angiotensin II can stimulate suprarenal gland release aldosterone to make vasoconstriction simultaneously, causes elevation of blood pressure.AngII is the strongest known one of active substance that boosts.

In addition, ACE has the degraded bradykinin again makes the function of its inactivation, because the effect that bradykinin has vasodilation, diuresis, brings high blood pressure down, so can cause increased blood pressure indirectly behind the bradykinin inactivation.ACE is present in the surface of endothelial cellular membrane in a large number, and endogenous AngI and bradykinin all can be transformed by it in the blood, causes increased blood pressure from two aspect effects.People are according to this constructional feature design of ACE and synthesized many angiotensin converting enzyme inhibitors, play antihypertensive function by suppressing angiotensin-converting enzyme ^[1-4]

General AC EI compounds all has more than five the binding site with ACE: the one, and the carboxyl of proline(Pro) is ionic linkage with the positively charged ion position of ACE and combines; The 2nd, the hydrogen supply position among intermediary ketonic oxygen (CO) and the ACE is hydrogen bonded; The 3rd, the Zn of the sulfydryl on the carbochain, carboxyl or phosphono and ACE ²⁺The position combination; Other are additional binding site.As shown in drawings:

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) ^[5,6]

They in bioavailability, plasma half-life, excretion pathway, distribution, and each is different in aspect such as ACE bonded avidity.Although ACEI with oral effectively, hypertension is effective and extensive concern lasting, advantage has been subjected to international and domestic the world of medicine such as therapeutic domain is wide ^[7,8], but also being no lack of negative report, after some patient took, some adverse drug reactions relevant with compound structure had appearred, as in coughing, the most common with captopril and enalapril, incidence is at 5%-15%, each country is slightly different: wherein the U.S. 19%, Japan 10%, China 16.8%; Asthma, bone marrow depression, vasodilation, itch and Oncocytosis etc. ^[9,10], caused that people more and more pay close attention to.How seeking and synthesizing outstanding ACEI is a very active field studying cardiovascular disorder.

The present invention designs synthetic route based on the basic structure of enalapril.We change its alanyl into tauryl, proline(Pro) and partly are replaced by thiazolidinecarboxylic acid and derivative thereof in synthetic route, obtain a series of N-[2-(1-ethoxy acyl group-3-phenylpropyl alcohol amino)-tauryl]-thiazolidinecarboxylic acid and derivative thereof.And by drug screening, novel ACEI efficient in the hope of obtaining, low toxicity.On pharmacology, thiazolidinecarboxylic acid is proved to be has effect such as protect the liver, antitumor ^[11-13], 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 ^[14], 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.

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 4 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 3rd, coupling (change) closes other compound or the group of antihypertensive active on traditional ACEI compound molecule; 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, structure is as follows:

Wherein R is:

Synthetic route 1:

Synthetic route 2:

Description of drawings

The dummy model in accompanying drawing ACE active function site: hydrophobic pocket (a) adds binding site (b)

Embodiment

Experimental procedure is as follows:

Synthesizing of thiazolidinecarboxylic acid and derivative thereof ^[15]

With L-cysteine hydrochloride, K _AC, the second alcohol and water mixes by a certain percentage, adds aldehyde compound, stir, crystallization, suction filtration, washing, drying, crude product, refining, drying, white crystal.

Synthesizing of thiazolidine acid benzyl ester ^[16]

Thiazolidinecarboxylic acid and derivative thereof are suspended in the benzylalcohol, and ice bath stirs and to drip thionyl chloride down, and reaction finishes decompression and steams thionyl chloride, filter, the filtrate washing, the saturated potassium carbonate adjust pH, dichloromethane extraction, dry organic layer, revolve steam compound.

The generation of dipeptides

The BOC-taurine is dissolved among the THF, adds HoBt, thiazolidinecarboxylic acid and derivant hydrochloric acid salt and N-Ethylmorphine quinoline, under agitation add the THF solution of DCC, filter concentrating under reduced pressure.Residue is dissolved in the ethyl acetate, uses saturated NaHCO successively ₃, 2N citric acid, NaHCO ₃Be washed till neutrality with saturated NaCl.Drying, concentrating under reduced pressure gets product.

Removing of protecting group

To join in the HCl-EtOAc solution by the compound that the reaction of last step generates.Stir, treat that the BOC reaction finishes after, be spin-dried for, the EtOAc extraction, drying promptly gets compound.

The preparation of 2-benzene monobromethane

In reaction flask, add the vitriol oil, Hydrogen bromide, stir, add 2 phenylethyl alcohol, stir, gradation adds the vitriol oil again, and heated and stirred is used concentrated hydrochloric acid and water washing successively, with normal hexane extraction, washing, the Calcium Chloride Powder Anhydrous drying reclaims solvent, and 93～96 ℃ cut is collected in distillation, gets liquid product.

The preparation of α-ketone group ethyl phenylbutyrate ^[17]

In the dry reaction bottle, add oxalic acid diethyl ester, tetrahydrofuran (THF), stir, cool off, Grignard reagent is dissolved in tetrahydrofuran (THF) drops to above-mentioned solution, use dichloromethane extraction.Dry organic layer, 105～110 ℃/0.03～0.04kPa cut is collected in underpressure distillation, gets product.

The preparation of target compound

In the dry reaction bottle, add tauryl-thiazolidinecarboxylic acid and derivative, sodium hydroxide and ethanolic soln, α-ketone group ethyl phenylbutyrate and a little molecular sieve, stir under the room temperature, add Lei Shi nickel, logical hydrogen filters.Reclaim catalyzer, decompression recycling ethanol adds entry and ethyl acetate in residue, add sodium hydroxide and transfer pH, tell organic layer, the water layer acidifying, add sodium-chlor, ethyl acetate extraction merges organic layer, washs with saturated nacl aqueous solution, decompression and solvent recovery, room temperature is placed, and separates out solid, and filtration drying gets crude product.Recrystallization gets pure product.

Reference

[1]Morrell，Nicholas?W.；Danilov，Sergei?M.；Satyan，Krishna?B.；Morris，Kenneth?G..Right?ventricularangiotensin?converting?enzyme?activity?and?expression?is?increased?during?hypoxic?pulmonaryhypertension.Cardiovascular?Research.3(1997).393-403

[2]Tamura，Tsunenobu；Johanning，Gary?L.；Goldenberg，Robert?L.；Johnston，Kelley?E.；Effect?ofangiotensin-converting?enzyme?gene?polymorphism?on?pregnancy?outcome，enzyme?activity，and?zincconcentration.Obstetrics?&?Gynecology.88(1996).497-502

[3] 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.

[4] Zheng Hu. pharmaceutical chemistry [M]. Beijing: People's Health Publisher, 2004.

[5]Tan，L.B.；Williams，S.G.；Goldspink，D.F.From?CONSENSUS?to?CHARM-how?do?ACEI?and?ARBproduce?clinical?benefits?in?CHF？.International?Journal?of?Cardiology.94(2004).137-141

[6]Barthelemy，Christiane.；Eurin，Joelle.；Lechat，Philippe.；Masson，Francoise.；Cortines.The?mechanism?ofthe?angiotensin-converting?enzyme?inhibitor?quinapril?is?not?related?to?bradykinin?level?in?heart?tissue.Peptides.23(2002).1161-1169

[7] Fu Chunyan, the progress [J] of Zhou Xianliang .ACEI in the congestive heart failure treatment. Chinese molecular cardiology magazine, 2004,06:50-54.

[8] Ge Cairong, Qi Yuqin. the clinical application [J] of angiotensin converting enzyme inhibitor (ACEI). Chinese medicine research and clinical, 2003,10:41-42

[9] An Maozhu, Sun Jing. the untoward reaction of angiotensin converting enzyme inhibitor and control [J]. Chinese Hospitals pharmaceutical journal, 2000,2:127-128

[10] land Lam. angiotensin converting enzyme inhibitor causes cough side effect analysis [J]. Chinese cardiovascular diseases research magazine, 2004,01:43-44.

[11] Wang Wenxue, Zhou Siyuan, Liu quintessence .L-2-oxygen-4-thiazolidinecarboxylic acid is to the provide protection [J] of mouse toxic liver injury. Hygiene Toxicology magazine, 1998,03:21-22.

[12] Wang Wenxue, Zhou Siyuan .L-2-oxygen-4-thiazolidinecarboxylic acid is to the provide protection [J] of gsh expendable liver injury. Chinese J Pharmacol Toxicol, 1997,02:77.

[13] Liu Jiyun etc. the synthetic and Antitumor Effects [J] of thiazolidinecarboxylic acid compounds. medicine industry, 1988,19 (5): 203

[14] tribute Xiao Wei. the design of novel thiazole alkane-4-carboxylic-acid angiotensin-convertion enzyme inhibitor and synthetic [D]. Jinan: Shandong University, 2001.

[15] Xia Mingde, synthetic [J] of .L-Thioprolines such as Tang Weifang. Jiangsu chemical industry, 1994 (2): 8-9.

[16]H?T.Nagasawa，J?F.Cohen，A?M?Holleschau，Augmentation?of?Human?and?Rat?Lenticular?Glutathione?in?Vitroby?Prodrugs?of?γ-L-Glutamyl-L-cysteine.J.Med.Chem，1996(39)：1676-1681.

[17] Chen Fener. organic drug synthesis method, the first roll [M]. Beijing: Chinese Medicine science and technology goes out society, and 1999.

Claims (1)

1. the compound that relates in the document has had The pharmacological results preferably, the present invention carries out structural modification on this basis, according to the original new drug design concept, designed synthetic route, its target is to obtain novel antihypertensive medicament ACEI efficient, low toxicity.

N-[2-(1-ethoxy acyl group-3-phenylpropyl alcohol amino)-tauryl]-mentality of designing, synthetic route and the synthetic method thereof of thiazolidinecarboxylic acid and derivative thereof.

Under classify general formula compound as:

Wherein

Route map is as follows:

Route 1:

Route 2:

The synthetic method of each compound and derivative thereof is as follows in the above-mentioned route:

1, the synthetic method of compound in the route 1:

Synthesizing of thiazolidinecarboxylic acid and derivative thereof

With L-cysteine hydrochloride, KA _C, the second alcohol and water mixes by a certain percentage, adds aldehyde compound, stir, crystallization, suction filtration, washing, drying, crude product, refining, drying, white crystal.

Synthesizing of thiazolidine acid benzyl ester

Thiazolidinecarboxylic acid and derivative thereof are suspended in the benzylalcohol, and ice bath stirs and to drip thionyl chloride down, and reaction finishes decompression and steams thionyl chloride, filter, the filtrate washing, the saturated potassium carbonate adjust pH, dichloromethane extraction, dry organic layer, revolve steam compound.

The generation of dipeptides

The BOC-taurine is dissolved among the THF, adds HoBt, thiazolidine acid esters and derivant hydrochloric acid salt and N-Ethylmorphine quinoline, under agitation add the THF solution of DCC, filter concentrating under reduced pressure.Residue is dissolved in the ethyl acetate, uses saturated NaHCO successively ₃, 2N citric acid, NaHCO ₃Be washed till neutrality with saturated NaCl.Drying, concentrating under reduced pressure gets product.

Removing of protecting group

To join in the HCl-EtOAc solution by the compound that the reaction of last step generates.Stir, treat that the BOC reaction finishes after, be spin-dried for, the EtOAc extraction, drying promptly gets compound.

2, the synthetic method of compound in the route 2:

The preparation of 2-benzene monobromethane

In reaction flask, add the vitriol oil, Hydrogen bromide, stir, add 2 phenylethyl alcohol, stir, gradation adds the vitriol oil again, and heated and stirred is used concentrated hydrochloric acid and water washing successively, with normal hexane extraction, washing, the Calcium Chloride Powder Anhydrous drying reclaims solvent, and 93～96 ℃ cut is collected in distillation, gets liquid product.

The preparation of α-ketone group ethyl phenylbutyrate

In the dry reaction bottle, add oxalic acid diethyl ester, tetrahydrofuran (THF), stir, cool off, Grignard reagent is dissolved in tetrahydrofuran (THF) drops to above-mentioned solution, use dichloromethane extraction.Dry organic layer, 105～110 ℃/0.03～0.04kPa cut is collected in underpressure distillation, gets product.

The preparation of target compound

In the dry reaction bottle, add tauryl-thiazolidinecarboxylic acid and derivative, sodium hydroxide and ethanolic soln, α-ketone group ethyl phenylbutyrate and a little molecular sieve, stir under the room temperature, add Lei Shi nickel, logical hydrogen filters.Reclaim catalyzer, decompression recycling ethanol adds entry and ethyl acetate in residue, add sodium hydroxide and transfer pH, tell organic layer, the water layer acidifying, add sodium-chlor, ethyl acetate extraction merges organic layer, washs with saturated nacl aqueous solution, decompression and solvent recovery, room temperature is placed, and separates out solid, and filtration drying gets crude product.Recrystallization gets pure product.

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