CN104447899B - A kind of intermediate of the compound for preparing renin angiotensin aldosterone system double inhibitor - Google Patents

A kind of intermediate of the compound for preparing renin angiotensin aldosterone system double inhibitor Download PDF

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CN104447899B
CN104447899B CN201410833796.9A CN201410833796A CN104447899B CN 104447899 B CN104447899 B CN 104447899B CN 201410833796 A CN201410833796 A CN 201410833796A CN 104447899 B CN104447899 B CN 104447899B
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CN104447899A (en
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林娇华
何人宝
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ZHEJIANG YONGTAI TECHNOLOGY Co Ltd
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ZHEJIANG YONGTAI TECHNOLOGY Co Ltd
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Abstract

The present invention relates to a kind of for preparing the midbody compound of the compound of RAA (RAAS) system doubling inhibitor, wherein said RAAS system doubling inhibitor can be used for treating the disease relevant to RAS system, including hypertension, heart disease etc..

Description

Intermediate for preparing compound of renin-angiotensin-aldosterone system dual inhibitor
Technical Field
The present invention relates to an intermediate compound useful for preparing a compound which is a dual inhibitor of the renin-angiotensin-aldosterone (RAAS) system, wherein said dual inhibitor of the RAAS system is useful in the treatment of diseases associated with the RAS system, including hypertension, heart disease, and the like.
Background
The renin-angiotensin-aldosterone system (RAAS) is a complex, highly effective system necessary to regulate blood flow, electrolyte balance, and arterial blood pressure. The two major components of this system are renin and angiotensin transferase. Renin is an aspartyl protease which can convert angiotensinogen produced in the liver into Angiotensin I, and Angiotensin I is converted into Angiotensin ii by Angiotensin I Converting Enzyme (ACE), and finally converted into Angiotensin iii which can promote aldosterone secretion, and inactivated. Angiotensin II is a peptide vasoconstrictor with strong action, can promote the release of norepinephrine from nerve endings, and can promote the growth of vascular smooth muscle and the reconstruction of cardiac structure by activating the expression of proto-oncogenes c-jun, c-fos, c-myc, egr-1 and the like, thereby playing an important role in hypertension.
Angiotensin ii is a very powerful vasoconstrictor with a blood pressure-raising efficacy that is 50 times that of norepinephrine. Both angiotensin I converting enzyme inhibitors (ACEI) and angiotensin II receptor Antagonists (ARB) inhibit the production of angiotensin II, thereby effectively dilating blood vessels and lowering blood pressure, and have been widely used in the treatment of hypertension and related diseases.
Both ACEI and ARB act on RAAS and cannot be used in combination theoretically. However, clinical observations show that the combined application of ACEI and ARB has better effect on reducing urine protein, and random control experiments also obtain the same result. 93% of patients in the Val-Heft study were combined with ACEI, and the results showed: the morbidity, the mortality and the hospitalization rate of the combined application of the valsartan and the ACEI are reduced, and the heart failure symptom and the LVEF are better than those of the single ACEI. The CHARM-Add trial for patients with chronic heart failure who have taken ACEI (and beta blocker), the addition of candesartan can further reduce the risk of cardiovascular death and hospitalization by 15%. Both ARB and ACEI block the adverse effects of RAAS, the therapeutic mechanisms are different, and the combined use of ACEI and ARB may produce a synergistic effect, but the general significance remains doubtful. The present inventors have surprisingly found a dual inhibitor which acts on the RAAS system without the risk of the combined use of ACEI and ARB.
Disclosure of Invention
The present invention provides an intermediate compound for preparing a dual inhibitor of RAAS system having angiotensin I converting enzyme inhibitory action and angiotensin II receptor antagonistic action, which can be used for preventing or treating diseases associated with RAAS system, including hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications caused by diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intraocular pressure, atherosclerosis, restenosis after angioplasty, complications after vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, pulmonary fibrosis, scleroderma, complications after vascular or cardiac surgery, erectile dysfunction, aldosterone deficiency, and/or side effects, Anxiety, cognitive disorders, complications resulting from treatment with immunosuppressive agents, and other diseases known to be associated with the renin-angiotensin system.
An object of the present invention is to provide a compound represented by the following formula (III), a stereoisomer thereof, or a salt thereof:
wherein,
x represents-NH-, -S-or-O-;
n is 0 or 1;
R1represents hydrogen or C1-6Alkyl radical, said C1-6The alkyl group may be selected from hydroxy, mercapto, amino, C1-6Alkyloxy, C1-6Alkylthio, aminocarbonyl, guanidino, indolyl and imidazolyl;
R2represents hydrogen, C1-6Alkyl radical, C3-6Cycloalkyl radical, C2-6Alkenyl or C2-6An alkynyl group;
R3represents hydrogen, C1-6Alkyl, aryl, heteroaryl, and heteroaryl,Wherein m represents 1, 2 or 3, R31Represents hydrogen or C1-6An alkyl group.
In one embodiment, X represents NH and n is 0.
In another embodiment, X represents S or O and n is 1.
In a preferred embodiment, R1Represents a methyl group.
In another preferred embodiment, R3Represents hydrogen, methyl, ethyl,
It is another object of the present invention to provide the use of a compound of formula (III) for the preparation of an antihypertensive medicament, which comprises the steps of:
contacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (I);
wherein,
x represents-NH-, -S-or-O-;
y represents a bond or-CH2O-；
Z representsOr
n is 0 or 1;
R1represents hydrogen or C1-6Alkyl radical, said C1-6The alkyl group may be selected from hydroxy, mercapto, amino, C1-6Alkyloxy, C1-6Alkylthio, aminocarbonyl, guanidino, indolyl and imidazolyl;
R2represents hydrogen, C1-6Alkyl radical, C3-6Cycloalkyl radical, C2-6Alkenyl or C2-6An alkynyl group;
R3represents hydrogen, C1-6Alkyl, aryl, heteroaryl, and heteroaryl,Wherein m represents 1, 2 or 3, R31Represents hydrogen or C1-6An alkyl group;
R4represents an acidic group, preferably a carboxyl group, a phosphoric group, a sulfonic group or a tetrazolyl group;
R5represents C1-6Alkyl-acyl;
R6represents hydrogen or C1-6Alkyl radical, said C1-6The alkyl group may be selected from hydroxy, mercapto, amino, C1-6Alkyloxy, C1-6Alkylthio, aminocarbonyl, guanidino, indolyl and imidazolyl;
R7represents the same or different 1-2 groups selected from hydrogen, halogen, cyano, carboxyl, C1-6Alkyl or C1-6A radical of an alkoxy group.
The compounds of formula (I) prepared according to the process of the present invention are useful for the prevention or treatment of diseases associated with the RAAS system, including hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intraocular pressure, atherosclerosis, restenosis following angioplasty, complications following vascular or cardiac surgery, erectile dysfunction, aldosteronism, pulmonary fibrosis, scleroderma, anxiety, cognitive disorders, complications resulting from treatment with immunosuppressive agents, and other diseases known to be associated with the renin-angiotensin system.
General preparation method
In one embodiment of the present invention, the compound of formula (III) is obtained by condensing an acid chloride represented by formula (V) with an alcohol represented by formula (IV):
in another embodiment, the compound of formula (V) is prepared by the following process: condensing an acid chloride of formula (VII) with a proline derivative of formula (VIII) to form a compound of formula (VI), followed by treatment with a chlorinating agent to form a compound of formula (V):
wherein R is1-R3X, n are as defined above.
When used, the compound of formula (II) of the present invention can be prepared by the following process: condensing a bromide of formula (IX) with a compound of formula (X) to form a compound of formula (II):
preferably, the first and second electrodes are formed of a metal,
a) when Z representsAnd Y represents a bond, the bromide of formula (IX) is condensed with a compound of formula (XI) and then treated with a catalyst containing R5Acylation of the group with an acylating agent:
or
b) When Z representsAnd Y represents-CH2O-, treating the compound of formula (XIV) with phosgene to obtain a compound of formula (IIb):
or
c) When Z representsAnd Y represents a chemical bond, oxidizing the compound of formula (XIII) with an oxidizing agent to a carboxylic acid compound of formula (XIV), followed by treatment with a chlorinating agent to give a compound of formula (IIc):
the oxidizing agent can be any suitable oxidizing agent, preferably a salt of a perhalogenate (e.g., sodium periodate, sodium perchlorate), potassium permanganate, potassium dichromate, a PCC oxidizing agent, a Jones reagent, ruthenium tetroxide, and the like. The chlorinating agent is preferably thionyl chloride, phosphorus trichloride, phosphorus pentachloride and the like.
Wherein the compound of formula (XIII) is prepared by condensing a bromide of formula (IX) with a compound of formula (XV):
wherein R is4-R7Y, Z are as defined above.
Alternatively, the compounds of formulae (II) to (XV) above may all carry a protecting agent, suitable examples for protecting groups being well known in the art.
When the compounds of the above formulae (II) to (XV) have a protecting agent, a step of removing the protecting group is further included.
Unless otherwise specified, "alkyl" as used herein is intended to include branched or straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-6Alkyl "or" C1-C6Alkyl "represents a linear or branched alkyl group having the indicated number of carbon atoms, including all isomers. C1-6Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
Similarly, "cycloalkyl" is intended to include cyclic saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, "C3-6Cycloalkyl radicals "or" C3-C6Cycloalkyl "represents a cyclic alkyl group having the indicated number of carbon atoms, including all isomers. C3-6Examples of alkyl groups include cyclo-n-propyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
Salts of the compounds of the present invention include pharmaceutically acceptable salts, including salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, phosphoric acid, nitric acid, and the like; addition salts with organic acids, including acetates, adipates, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethylsulfonates, fumarates, glucoheptonates, glycerophosphates, hemisulfates, heptanoates, caproates, hydrochlorides, hydrobromides, hydroiodide, 2-hydroxyethyl sulfonate, lactate, maleate, methyl sulfonate, 2-naphthyl sulfonate, nicotinate, nitrate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate; such as quaternary ammonium salts of inorganic or organic acids or bases; the acid-base type salts include ammonium salts, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, salts with organic bases such as dicyclohexylamine salt, N-methyl-D-glucosamine, and salts with amino acids such as arginine, lysine, and the like. Similarly, the basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromide, and iodide; dialkyl sulfates such as dimethyl, diethyl, dibutyl; and diamyl sulfate, long chain halides such as undecyl, dodecyl, tetradecyl, and octadecyl chlorides, bromides and iodides, arylalkyl halides such as benzyl and phenethyl bromides, and others.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Preparation of the Compound of formula (III)
Example 1: preparation of methyl ((S) -3-mercapto-2-methylpropionyl) -L-proline (Compound III-1)
Adding L-proline (2.8mmol) and 8% NaOH solution (2.8mmol) into a four-neck flask, stirring to dissolve, reducing the temperature to 0 ℃, starting to dropwise add (S) -3-mercapto-2-methylpropanoyl chloride (3.5mmol), simultaneously maintaining the pH of the reaction system at 7.5-9 by using 8% NaOH solution, keeping the temperature at 0-5 ℃, after the dropwise addition of the acyl chloride is finished, continuously dropwise adding 8% NaOH solution, and adjusting the pH of the reaction system to 7 until the pH is unchanged. Stirring at room temperature for 3 hr, neutralizing with hydrochloric acid at low temperature, extracting with ethyl acetate, mixing organic phases, washing with 10% NaCl solution, and anhydrous MgSO4Drying and filtering to remove the drying agent. The solvent was recovered to give the title compound. The molecular formula is as follows: c9H15NO3S; mass spectrometry (m/z): 217.08 (100.0%); elemental analysis: c, 49.75; h, 6.96; n, 6.45; o, 22.09; s, 14.75.
Example 2: preparation of (3-hydroxy-6-methoxy-4, 5-dinitrooxytetrahydro-2H-pyran-2-yl) - ((S) -3-mercapto-2-methylpropanoyl) -L-prolinate (Compound III-2)
Adding the ethyl acetate solution of the compound III-1 into a four-neck flask, slowly dropwise adding thionyl chloride with an equal molar amount while stirring at room temperature, heating to 58 ℃ after dropwise adding, continuously stirring for reaction for 5 hours, and distilling under reduced pressure to recover the solvent. The product was dissolved in DMF, potassium carbonate was added, stirred to dissolve, then 5-hydroxy-6-hydroxymethyl-2-methoxytetrahydro-2H-pyran-3, 4-dinitrate was added and the mixture was stirred at 70 ℃ for 2 hours. After the reaction is finished, adding water into the mixture, extracting the mixture by using ethyl acetate, and separating the mixture by using silica gel column chromatography to obtain a product. The molecular formula is as follows: c16H25N3O12S; mass spectrometry (m/z): 483.12 (100.0%), 484.12 (18.9%); elemental analysis: c, 39.75; h, 5.21; n, 8.69;O,39.71；S,6.63。
example 3: preparation of L-alanyl-L-proline (Compound III-3)
L-alanyl-L-proline is obtained by condensation reaction of L-alanyl chloride instead of (S) -3-mercapto-2-methylpropanoyl chloride with L-proline under alkaline conditions according to the same procedure as in example 1. The molecular formula is as follows: c8H14N2O3(ii) a Mass spectrometry (m/z): 186.20 (100.0%); elemental analysis: c, 51.60; h, 7.58; n, 15.04; and O, 25.78.
Example 4: preparation of L-alanyl-L-proline 2, 3-dinitrooxy glyceride (Compound III-4)
Adding the ethyl acetate solution of the compound III-3 into a four-neck flask, slowly dropwise adding thionyl chloride with equal molar quantity while stirring at room temperature, heating to 60 ℃ after dropwise adding, continuously stirring for reaction for 5 hours, and distilling under reduced pressure to recover the solvent. Dissolving the product in DMF, adding potassium carbonate, stirring to dissolve, then adding (3aS,6aR) -6-hydroxy-hexahydrofuro [3,2-b ]]Furan-3-nitrate and the mixture was stirred at 70 ℃ for 2 hours. After the reaction is finished, adding water into the mixture, extracting the mixture by using ethyl acetate, and separating the mixture by using silica gel column chromatography to obtain a product. The molecular formula is as follows: c14H21N3O8Mass spectrometry (m/z): 359.13 (100.0%); elemental analysis: c, 46.80; h, 5.89; n, 11.69; and O, 35.62.
Similarly, compounds III-5 to 10 (see Table 1) can be prepared by condensing different amino acid derivatives with L-proline and then esterifying with the corresponding alcohol.
TABLE 1
Application examples
Preparation of the Compound of formula (II)
Preparation of N-pentanoyl-N- (4- (2- (1-trityl-1H-tetrazol-5-yl) phenyl) methyl-L-valinoyl chloride (compound II-1)
Step 1, preparation of N- (4- (2- (1-trityl-1H-tetrazole-5-yl) phenyl) methyl-L-valine
Adding potassium carbonate (12.5g) and acetonitrile (85mL) into a 250mL three-neck flask, adding L-valine (5.0g), stirring, reacting for 0.5h, adding 2-N-trityl-5- (4' -bromomethyl biphenyl-2-yl) tetrazole (16.7g), heating to reflux for 8h, cooling to room temperature, filtering, washing a filter cake with 10mL of acetonitrile, combining filtrates, carrying out reduced pressure rotary evaporation, recovering a solvent, adding 100mL of ethyl acetate into a residue, washing an ethyl acetate layer with brine (30mL × 2), drying the ethyl acetate layer with anhydrous sodium sulfate, filtering, and recovering the solvent to obtain the title compound38H35N5O2Mass spectrometry (m/z): m/z 593.28 (100.0%), 594.28 (43.0%). Element classificationAnd (3) analysis: c, 76.87; h, 5.94; n, 11.80; and O, 5.39.
Step 2, preparation of N-valeryl-N- (4- (2- (1-trityl-1H-tetrazol-5-yl) phenyl) methyl-L-valine
Dissolving the product obtained in the step 1 in toluene (100mL), adding sodium bicarbonate (4.1g), stirring for 0.5h, cooling to 5 ℃, dropwise adding valeryl chloride (4.6mL), stirring at room temperature for 30h after the addition, adding a 10% sodium bicarbonate solution (30mL), stirring at room temperature for 4h for layering, washing a toluene layer with brine (30mL × 2), drying with anhydrous sodium sulfate, filtering, and recovering a solvent to obtain a title compound with a molecular formula of C43H43N5O3Mass spectrometry (m/z): 677.34 (100.0%), 678.34 (47.1%).
Elemental analysis: c, 76.19; h, 6.39; n, 10.33; and O, 7.08.
Step 3, preparation of N-valeryl-N- (4- (2- (1-trityl-1H-tetrazol-5-yl) phenyl) methyl-L-valinoyl chloride
The product of step 2 (8.9mmoL) was charged into a four-necked flask, and an equimolar amount of thionyl chloride was slowly dropped while stirring at room temperature, and the generated gas was absorbed by a sodium hydroxide or potassium hydroxide solution. After the dropwise addition, the temperature is raised to 70 ℃, and the stirring reaction is continued for 6 hours. Distillation under reduced pressure gave the title compound. The molecular formula is as follows: c43H42N5O2Cl, Mass Spectrometry (m/z): 6695.30 (100.0%), 696.31 (47.1%), 697.30 (32.8%).
Elemental analysis: c, 74.17; h, 6.08; cl, 5.09; n, 10.06; and O, 4.60.
Preparation of N-pentanoyl-N- (4- (2- (1-trityl-1H-tetrazol-5-yl) phenyl) methyl-L-leucyl chloride (compound II-2)
Step 1, preparation of N- (4- (2- (1-trityl-1H-tetrazole-5-yl) phenyl) methyl-L-leucine
Adding potassium carbonate (12.5g) and acetonitrile (85mL) into a 250mL three-neck flask, adding L-leucine (5.6g), stirring, reacting for 1h, adding 2-N-trityl-5- (4' -bromomethyl biphenyl-2-yl) tetrazole (16.7g), heating to reflux for 8h, cooling to room temperature, filtering, washing a filter cake with 10mL of acetonitrile, combining filtrates, carrying out reduced pressure rotary evaporation, recovering a solvent, adding 100mL of ethyl acetate into a residue, washing an ethyl acetate layer with brine (30mL × 2), drying an ethyl acetate layer with anhydrous sodium sulfate, filtering, and recovering the solvent to obtain the title compound39H37N5O2(ii) a Mass spectrometry (m/z): 607.29 (100.0%), 608.30 (42.7%); elemental analysis: c, 77.07; h, 6.14; n, 11.52; and O, 5.26.
Step 2, preparing N-valeryl-N- (4- (2- (1-trityl-1H-tetrazol-5-yl) phenyl) methyl-L-leucine
Dissolving the product obtained in the step 1 in toluene (100mL), adding sodium bicarbonate (4.1g), stirring for 0.5h, cooling to 5 ℃, dropwise adding valeryl chloride (4.6mL), stirring at room temperature for 30h after the addition, adding a 10% sodium bicarbonate solution (30mL), stirring at room temperature for 4h for layering, washing a toluene layer with brine (30mL × 2), drying with anhydrous sodium sulfate, filtering, and recovering a solvent to obtain a title compound with a molecular formula of C44H45N5O3(ii) a Mass spectrometry (m/z): 691.35 (100.0%), 692.36 (48.2%); elemental analysis: c, 76.38; h, 6.56; n, 10.12; and O, 6.94.
Step 3, preparation of N-valeryl-N- (4- (2- (1-trityl-1H-tetrazol-5-yl) phenyl) methyl-L-leucine acyl chloride
The product of step 2 (9.0mmoL) was charged into a four-necked flask, and an equimolar amount of thionyl chloride was slowly dropped while stirring at room temperature, and the generated gas was absorbed by a sodium hydroxide or potassium hydroxide solution. After the dropwise addition, the temperature is raised to 65 ℃, and the stirring reaction is continued for 7 hours. Distillation under reduced pressure gave the title compound. The molecular formula is as follows: c44H44ClN5O2(ii) a Mass spectrometry (m/z): 709.32 (100.0%), 710.32 (50.0%); elemental analysis: c, 74.40; h, 6.24; cl, 4.99; n, 9.86; and O, 4.50.
Preparation of N-pentanoyl-N- (4- (2- (1-trityl-1H-tetrazol-5-yl) phenyl) methyl-L-serine acyl chloride (compound II-3)
Step 1, preparation of N- (4- (2- (1-trityl-1H-tetrazole-5-yl) phenyl) methyl-L-serine
Adding potassium carbonate (12.5g) and acetonitrile (85mL) into a 250mL three-neck flask, adding L-serine (4.5g), stirring, reacting for 1h, adding 2-N-trityl-5- (4' -bromomethyl biphenyl-2-yl) tetrazole (16.7g), heating to reflux for 8h, cooling to room temperature, filtering, washing a filter cake with 15mL of acetonitrile, combining filtrates, carrying out reduced pressure rotary evaporation, recovering a solvent, adding 100mL of ethyl acetate into a residue, washing an ethyl acetate layer with brine (30mL × 2), drying an ethyl acetate layer with anhydrous sodium sulfate, filtering, and recovering the solvent to obtain the title compound, wherein the molecular formula is C36H31N5O3(ii) a Mass spectrometry (m/z): 581.24 (100.0%), 582.25 (39.4%); elemental analysis: c, 74.34; h, 5.37; n, 12.04; and O, 8.25.
Step 2, preparation of N-valeryl-N- (4- (2- (1-trityl-1H-tetrazol-5-yl) phenyl) methyl-L-serine
Dissolving the product obtained in the step 1 in toluene (100mL), adding sodium bicarbonate (4.1g), stirring for 0.5h, cooling to 5 ℃, dropwise adding valeryl chloride (4.6mL), stirring at room temperature for 30h after the addition, adding a 10% sodium bicarbonate solution (30mL), stirring at room temperature for 4h for layering, washing a toluene layer with brine (30mL × 2), drying with anhydrous sodium sulfate, filtering, and recovering a solvent to obtain a title compound with a molecular formula of C41H39N5O4(ii) a Mass spectrometry (m/z): 665.30 (100.0%), 666.30 (46.3%); elemental analysis: c,73.96；H,5.90；N,10.52；O,9.61。
Step 3, preparation of N-valeryl-N- (4- (2- (1-trityl-1H-tetrazol-5-yl) phenyl) methyl-L-serine acyl chloride
The product of step 2 (8.9mmoL) was charged into a four-necked flask, and an equimolar amount of thionyl chloride was slowly dropped while stirring at room temperature, and the generated gas was absorbed by a sodium hydroxide or potassium hydroxide solution. After the dropwise addition, the temperature is raised to 65 ℃, and the stirring reaction is continued for 7 hours. Distillation under reduced pressure gave the title compound. The molecular formula is as follows: c41H38ClN5O3(ii) a Mass spectrometry (m/z): 683.27 (100.0%), 684.27 (44.9%); elemental analysis: c, 71.97; h, 5.60; cl, 5.18; n, 10.24; and O, 7.01.
Preparation of N2-pentanoyl-N2- (4- (2- (1-trityl-1H-tetrazol-5-yl) phenyl) methyl-L-glutamineacyl chloride (compound II-4)
Step 1, preparation of N2- (4- (2- (1-trityl-1H-tetrazol-5-yl) phenyl) methyl-L-glutamine
Adding potassium carbonate (12.5g) and acetonitrile (85mL) into a 250mL three-neck flask, adding L-glutamine (6.2g), stirring, reacting for 1h, adding 2-N-trityl-5- (4' -bromomethyl biphenyl-2-yl) tetrazole (16.7g), heating to reflux for 8h, cooling to room temperature, filtering, washing a filter cake with 15mL of acetonitrile, combining filtrates, carrying out reduced pressure rotary evaporation, recovering a solvent, adding 100mL of ethyl acetate into a residue, washing an ethyl acetate layer with brine (30mL × 2), drying an ethyl acetate layer with anhydrous sodium sulfate, filtering, and recovering the solvent to obtain the title compound, wherein the molecular formula is C38H34N6O3(ii) a Mass spectrometry (m/z): 622.27 (100.0%), 623.27 (43.4%); elemental analysis: c, 73.29; h, 5.50; n, 13.50; and O, 7.71.
Step 2, preparation of N2-pentanoyl-N2- (4- (2- (1-trityl-1H-tetrazol-5-yl) phenyl) methyl-L-glutamine
Dissolving the product obtained in the step 1 in toluene (100mL), adding sodium bicarbonate (4.1g), stirring for 0.5h, cooling to 5 ℃, dropwise adding valeryl chloride (4.6mL), stirring at room temperature for 30h after the addition, adding a 10% sodium bicarbonate solution (30mL), stirring at room temperature for 4h for layering, washing a toluene layer with brine (30mL × 2), drying with anhydrous sodium sulfate, filtering, and recovering a solvent to obtain a title compound with a molecular formula of C43H42N6O4(ii) a Mass spectrometry (m/z): 706.33 (100.0%), 707.33 (47.1%); elemental analysis: c, 73.07; h, 5.99; n, 11.89; and O, 9.05.
Step 3, preparation of N2-pentanoyl-N2- (4- (2- (1-trityl-1H-tetrazol-5-yl) phenyl) methyl-L-glutamineacyl chloride
The product of step 2 (8.9mmoL) was charged into a four-necked flask, and an equimolar amount of thionyl chloride was slowly dropped while stirring at room temperature, and the generated gas was absorbed by a sodium hydroxide or potassium hydroxide solution. After the dropwise addition, the temperature is raised to 65 ℃, and the stirring reaction is continued for 7 hours. Distillation under reduced pressure gave the title compound. The molecular formula is as follows: c43H41ClN6O3(ii) a Mass spectrometry (m/z): 724.29 (100.0%), 725.30 (47.1%), 726.29 (33.0%); elemental analysis: c, 71.21; h, 5.70; cl, 4.89; n, 11.59; and O, 6.62.
Preparation of (2-butyl-4-chloro-1- ((2'- (1-trityl-1H-tetrazol-5-yl) - [1,1' -biphenyl ] -4-yl) methyl) -1H-imidazol-5-yl) methanolic chloroformate (Compound II-5)
Slowly dripping the mixed solution of the losartan and the triethylamine into a dichloromethane solution of the solid phosgene at a low temperature (the mol ratio of the losartan to the solid phosgene is 1:0.5), and reacting for 1 hour at a temperature of 10 ℃ after the dripping is finished. After the reaction is finished, slowly dropwise adding quantitative water into the reaction liquid to decompose unreacted solid phosgene, and washing with water until the pH value is 5-6. Triethylamine was then added to the reaction mixture, and mixed with stirring, a solution of trityl chloride in dichloromethane was added, and the resulting reaction mixture was stirred at room temperature. The reaction mixture was washed with water, dried over magnesium sulfate, filtered, and distilled under reduced pressure to give the title compound.
The molecular formula is as follows: c42H36Cl2N6O2(ii) a Mass spectrometry (m/z): 726.23 (100.0%), 728.22 (63.9%), 727.23 (45.9%); elemental analysis: c, 69.32; h, 4.99; cl, 9.74; n, 11.55; and O, 4.40.
Preparation of 2-butyl-4-chloro-1- ((2'- (1-trityl-1H-tetrazol-5-yl) - [1,1' -biphenyl ] -4-yl) methyl) -1H-imidazole-5-carbonyl chloride (Compound II-6)
Step A: to a four-necked flask was added water (100ml), potassium hydroxide (152.4mmol), followed by losartan (10.9mmol), sodium periodate (25.9mmol) and ruthenium (III) chloride monohydrate (0.5mmol) at 0 ℃ and the reaction mixture was stirred at 0 ℃ overnight. And filtering the reaction mixed solution. To the filtrate was added isopropanol with stirring, the solution was warmed to 25 ℃ and stirred for 2.5 hours, to which was added phosphoric acid, maintaining the temperature below 30 ℃. The mixture was stirred for 30 min and the resulting product was filtered, washed with water and the residue dried in vacuo to give 2-butyl-4-chloro-1- ((2'- (1H-tetrazol-5-yl) - [1,1' -biphenyl ] -4-yl) methyl) -1H-imidazole-5-carboxylic acid.
And B: to the dichloromethane solution of the product of step a was added triethylamine, followed by addition of a dichloromethane solution of trityl chloride, and the resulting reaction mixture was stirred at room temperature. Washing the reaction mixture with water, drying with magnesium sulfate, filtering, concentrating in vacuum, loading on a silica gel column, eluting with 20-80% acetone/n-hexane to obtain 2-butyl-4-chloro-1- { [ 2' - (2-trityl-2H-tetrazole-5-) biphenyl-4- ] methyl } -1H-imidazole-5-carboxylic acid.
And C: and (3) adding the ethyl acetate solution of the product obtained in the step (B) into a four-neck flask, slowly dropwise adding thionyl chloride with equal molar quantity while stirring at room temperature, heating to 55 ℃ after dropwise adding, continuously stirring for reaction for 6 hours, and carrying out reduced pressure distillation to recover the solvent to obtain a product compound II-2 which can be directly used for the next reaction without further separation.
The molecular formula is as follows: c41H34Cl2N6O; mass spectrometry (m/z): 696.22 (100.0%), 698.21 (63.9%), 697.22 (44.8%); elemental analysis: c, 70.59; h, 4.91; cl, 10.16; n, 12.05; o, 2.29.
Preparation of Compounds of formula (I)
Preparation of (3-hydroxy-6-methoxy-4, 5-dinitrooxytetrahydro-2H-pyran-2-yl) - (3- ((N- (4- (2- (1H-tetrazol-5-yl) phenyl) methyl) -N-pentanoyl-L-valyl) thio) -2-methylpropanoyl) -L-proline (compound I-1)
Adding the compound III-2(3.0mmol), potassium carbonate (3.0mmol) and DMF (100ml) into a four-neck flask, stirring to dissolve, reducing the temperature to 0 ℃, starting to dropwise add the compound II-1(3.0mmol), simultaneously maintaining the pH of the reaction system at 7.0-8.0 by using a potassium carbonate solution, keeping the temperature at 0 ℃, after the dropwise addition is finished, continuously dropwise adding the potassium carbonate solution, and adjusting the pH of the reaction system to 7 until the pH is unchanged. The reaction mixture was stirred at room temperature for 3 hours, to which was then added water (40ml), which was extracted with ethyl acetate to recover the solvent. The residue was adsorbed with silica gel and eluted with n-hexane/acetone to give the title compound.
The molecular formula is as follows: c40H52N8O14S; mass spectrometry (m/z): 900.32 (100.0%), 901.33 (44).6％)；
Elemental analysis: c, 53.33; h, 5.82; n, 12.44; o, 24.86; and S, 3.56.
1H-NMR(6d-DMSO)：7.96(2H),7.60(2H),7.47(2H),7.41(2H),6.33(1H),5.40(1H),4.88(1H),4.46(2H),4.06-4.33(5H),3.90(1H),3.70(1H),3.60(1H),3.46(2H),3.40(3H),2.95-3.21(2H),2.70(2H),2.20-2.43(2H),2.04(2H),1.97(2H),1.53(2H),1.38(2H),1.17(3H),0.96(6H),0.93(3H)。
Preparation of (3aR,6aS) -3- (N- ((2'- (1H-tetrazol-5-yl) - [1,1' -biphenyl ] -4-yl) methyl) -N-N-pentanoyl-L-leucyl-L-alanyl-L-prolineyloxy) -6- (nitrooxy) hexahydrofuro [3,2-b ] furan (Compound I-2)
In a similar manner to example 1, compound II-2 and compound III-4 were reacted in the presence of a basic agent such as potassium carbonate to give the title compound. The molecular formula is as follows: c39H50N8O10(ii) a Mass spectrometry (m/z): 790.36 (100.0%), 791.37 (43.1%); elemental analysis: c, 59.23; h, 6.37; n, 14.17; and O, 20.23.
1H-NMR(CDCl3)：8.32(1H),7.96(2H),7.60(2H),7.41-7.47(4H),6.33(1H),5.22(1H),4.64(1H),4.46(2H),4.44(1H),4.29(1H),4.14(4H),3.85(3H),3.46(2H),2.30(2H),1.97-2.05(4H),1.76(2H),1.38-1.53(8H),0.93(9H)。
Preparation of (3aR,6aS) -3- (N- ((2'- (1H-tetrazol-5-yl) - [1,1' -biphenyl ] -4-yl) methyl) -N-N-pentanoyl-L-serinyl-L-alanyl-L-prolineyloxy) -6- (nitrooxy) hexahydrofuro [3,2-b ] furan (Compound I-3)
To make sure thatIn a similar manner to example 1, Compound II-3 and Compound III-4 were reacted in the presence of a basic reagent such as potassium carbonate to give the title compound. The molecular formula is as follows: c36H44N8O11(ii) a Mass spectrometry (m/z): 764.31 (100.0%), 765.32 (39.9%); elemental analysis: c, 56.54; h, 5.80; n, 14.65; and O, 23.01.
1H-NMR(CDCl3)：8.30(1H),7.95(2H),7.59(2H),7.41-7.47(4H),6.32(1H),5.21(1H),4.95(1H),4.64(1H),4.54(1H),4.46(2H),4.29(1H),4.15(5H),3.85-3.99(4H),3.46(2H),2.32(1H),2.20(1H),1.97-2.05(4H),1.38-1.53(7H),0.92(3H)。
Preparation of (3aR,6aS) -3- (N2- ((2'- (1H-tetrazol-5-yl) - [1,1' -biphenyl ] -4-yl) methyl) -N2-N-pentanoyl-L-glutaminyl-L-alanyl-L-prolyloxy) -6- (nitrooxy) hexahydrofuro [3,2-b ] furan (Compound I-4)
In a similar manner to example 1, compound II-4 and compound III-4 were reacted in the presence of a basic agent such as potassium carbonate to give the title compound. The molecular formula is as follows: c38H47N9O11(ii) a Mass spectrometry (m/z): 805.34 (100.0%), 806.34 (44.8%); elemental analysis: c, 56.64; h, 5.88; n, 15.64; and O, 21.84.
1H-NMR(CDCl3)：8.32(1H),7.96(2H),7.60(2H),7.41-7.47(4H),7.03(2H),6.33(1H),5.22(1H),4.64(1H),4.45(3H),4.29(1H),4.15(4H),3.85(3H),3.46(2H),2.30(1H),1.92-2.05(9H),1.47-1.53(7H),0.93(3H)。
Preparation of (3aS,6aR) -6- (nitrooxy) hexahydrofuro [3,2-b ] furan-3-yl (((1- ((2'- (1H-tetrazol-5-yl) - [1,1' -biphenyl ] -4-yl) methyl) -2-butyl-4-chloro-1H-imidazol-5-yl) methoxy) carbonyl) -L-alanyl-L-prolinate (Compound I-5)
Adding the compound III-4(3.0mmol), potassium carbonate (3.0mmol) and DMF (100ml) into a four-neck flask, stirring to dissolve, reducing the temperature to 0 ℃, starting to dropwise add the compound II-5(3.0mmol), simultaneously maintaining the pH of the reaction system at 7.0-8.0 by using a potassium carbonate solution, keeping the temperature at 0 ℃, after the dropwise addition is finished, continuously dropwise adding the potassium carbonate solution, and adjusting the pH of the reaction system to 7 until the pH is unchanged. The reaction was stirred at room temperature for 3 hours, and then water was added thereto, followed by extraction with ethyl acetate and recovery of the solvent. The residue was adsorbed with silica gel and eluted with n-hexane/acetone to give the title compound.
The molecular formula is as follows: c37H42ClN9O10Mass spectrometry analysis: m/z 807.27 (100.0%), 808.28 (40.9%), 809.27 (33.3%); elemental analysis: c, 54.98; h, 5.24; cl, 4.39; n, 15.60; o, 19.79;1H NMR(CDCl3)：7.96(2H),7.60(2H),7.39(1H),7.34(4H),6.33(1H),5.46(2H),5.40(2H),5.22(1H),4.64(1H),4.29(1H),4.14(4H),3.85(3H),3.46(2H),2.87(2H),2.44(1H),2.19(1H),1.97-2.09(2H),1.59(2H),1.47(3H),1.30(2H),0.90(3H)。
preparation of (3aS,6aR) -6- (nitrooxy) hexahydrofuro [3,2-b ] furan-3-yl ((1- ((2'- (1H-tetrazol-5-yl) - [1,1' -biphenyl ] -4-yl) methyl) -2-butyl-4-chloro-1H-imidazol-5-yl) formyl) -L-alanyl-L-prolinate (Compound I-6)
Adding the compound III-4(3.0mmol), potassium carbonate (3.0mmol) and DMF (100ml) into a four-neck flask, stirring to dissolve, reducing the temperature to 0 ℃, starting to dropwise add the compound II-6(3.0mmol), simultaneously maintaining the pH of the reaction system at 7.0-8.0 by using a potassium carbonate solution, keeping the temperature at 0 ℃, after the dropwise addition is finished, continuously dropwise adding the potassium carbonate solution, and adjusting the pH of the reaction system to 7 until the pH is unchanged. The reaction was stirred at room temperature for 2.5 hours, and then water was added thereto, followed by extraction with ethyl acetate and recovery of the solvent. The residue was adsorbed with silica gel and eluted with n-hexane/acetone to give the title compound.
The molecular formula is as follows: c36H40ClN9O9(ii) a Mass spectrometry (m/z): 777.26 (100.0%), 778.27 (39.5%), 779.26 (33.1%); elemental analysis: c, 55.56; h, 5.18; cl, 4.56; n, 16.20; o, 18.50.
1H NMR(CDCl3)：9.38(1H),7.93(2H),7.62(2H),7.36(4H),6.35(1H),5.46(2H),5.22(1H),4.64(1H),4.29(1H),4.01-4.15(4H),3.87(3H),3.45(2H),2.87(2H),2.45(1H),2.18(1H),1.90-2.03(2H),1.59(2H),1.47(3H),1.30(2H),0.90(3H)。
Similarly, the following compounds (see Table 2) can be prepared by reacting compounds III-1 to 11 with compounds II-1 to 6 respectively in the presence of an alkaline reagent potassium carbonate:
TABLE 2
Biological examples
1. Assay for angiotensin II receptor antagonistic Activity
The assay was carried out according to the method disclosed by Wangxiaowei et al (determination of the activity of angiotensin II receptor antagonist, journal of Beijing medical university, Vol.30, No. 4, p.370, 1998).
In 0.35ml of rat liver cell membrane receptor reaction solutionAdding about 100 μ g of liver membrane protein, a fixed amount125Mixing I-angiotensin II receptor (about 5,000 count rate/min) with non-labeled angiotensin II receptor (0.045 ng-30 ng), adding 1 μ g angiotensin II receptor in non-specific tube, reacting at 25 deg.C for 70min, stopping reaction in water bath, collecting the bound angiotensin II receptor with a multi-head collector125The I-angiotensin II receptor is collected on glass fiber filter paper (pre-saturated with 1mg/L angiotensin II receptor), and each tube is washed with 5ml of washing liquid for 3-4 times. Measuring radioactivity with gamma counter, calculating IC50The value is obtained.
Experimental results show that the IC of the compounds I-1 to 14 of the above embodiments of the invention50≤2μmol。
2. Angiotensin converting enzyme I inhibition assay
The test was carried out by HPLC-ESI-MS method disclosed in Shenyuan et al (method for measuring angiotensin converting enzyme inhibitor inhibitory rate, 3 rd, page 212-216 of food science 2007). The results show that the IC of the compounds I-1 to 14 of the above examples of the present invention50≤1μmol。
3. Reactive nitrogen Radical (RNS) assay (diaminonaphthalene assay)
The detection of reactive nitrogen Radicals (RNS) in the form of S-nitrosothiols in the plasma of ethylenediaminetetraacetic acid (EDTA) rats was carried out by High Performance Liquid Chromatography (HPLC) fluorescence detection according to the method proposed by Kostka and Park (see Methods enzymol, Methods 1999, 301, 227-. The method is based on the detection of fluorescent 2, 3-naphthol triazoles (NATs) produced by the reaction between acidified 2, 3-Diaminonaphthalene (DAN) and the nitrosothiols (RSNOs) of the nitrosothiols released by mercury chloride mediated cleavage of the S-NO bond. And (3) carrying out chromatography on the reaction mixed liquid by using reverse-phase high performance liquid chromatography, and quantifying the analyzed fluorescence signal of the naphthol triazole (NAT) peak.
Plasma (20 microliters) was first diluted with water (20 microliters) in a 1:1 ratio in an untreated black polypropylene microtiter plate. Diaminonaphthalene (DAN) reagent (100 μ l per well, 100 μm diaminonaphthalene in 0.1N hydrochloric acid, 4mm mercuric chloride) was added and the microtiter plates were immediately sealed using an opaque pad, spun and incubated in the dark for 10 minutes. The plates were centrifuged (2000x g, 5 min) and cooled to 4 ℃ before High Performance Liquid Chromatography (HPLC) analysis. High Performance Liquid Chromatography (HPLC) was performed in an Agilent 1200 system using a cooled autosampler (4 ℃). The sample was chromatographed on a C8 column (Zorbax Eclipse XDB-C8, 4.6X 150 mm, 5 μm) using 67% methanol, 0.1% ammonium acetate as the mobile phase and gradient-free elution at a flow rate of 2 ml/min. Fluorescence of naphthotriazole was monitored at 450 nm with an excitation wavelength of 360 nm. A calibration curve was prepared in control plasma using sodium nitrite.
The active nitrogen radical levels of compounds I-1 to 14 of the above examples of the present invention peaked in about 1 hour, typically 0.1 to 30 micromolar, confirming that the nitroxyl compounds of the present invention generate nitric oxide in vivo, and thus respond to the administered test compounds.

Claims (4)

1. A compound represented by the formula (III):
wherein,
x represents-NH-, -S-or-O-;
n is 0 or 1;
R1represents a methyl group;
R2represents hydrogen;
R3represents
2. A compound according to claim 1, wherein X represents NH and n is 0.
3. A compound according to claim 1, wherein X represents S or O and n is 1.
4. A compound selected from:
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