CN104496969B - A kind of compound for renin angiotensin aldosterone system double inhibitor - Google Patents

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

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CN104496969B
CN104496969B CN201410827383.XA CN201410827383A CN104496969B CN 104496969 B CN104496969 B CN 104496969B CN 201410827383 A CN201410827383 A CN 201410827383A CN 104496969 B CN104496969 B CN 104496969B
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CN104496969A (en
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何人宝
王莺妹
邵鸿鸣
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ZHEJIANG YONGTAI TECHNOLOGY Co Ltd
ZHEJIANG YONGTAI PHARMACEUTICAL Co Ltd
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Abstract

nullA kind of compound for renin-angiotensin-aldosterone system double inhibitor，Can be used for treating the disease relevant to blocking RAS system，Including hypertension、Congestive heart failure、Pulmonary hypertension、Renal insufficiency、Renal ischaemia、Renal failure、Renal fibrosis、Cardiac Insufficiency、Cardiac hypertrophy、Cardiac fibrosis、Myocardial ischemia、Cardiomyopathy、Glomerulonephritis、Renal colic、The complication caused by diabetes such as nephropathy、Vascular lesion and neuropathy、Glaucoma、Intraocular pressure raises、Atherosclerosis、The restenosis that vascularization is postoperative、Blood vessel or the postoperative complication of Cardiac surgical procedures、Erection disturbance、Aldosteronism、Lungs fibrosis、Scleroderma、Anxiety、Cognitive disorder、By the complication caused by the treatment of immunosuppressant、And the disease that other known with described renin-angiotensin systems are associated.

Description

A kind of compound for renin angiotensin aldosterone system double inhibitor
Technical field
The present invention relates to a kind of compound for renin angiotensin aldosterone system double inhibitor, can be used for Treat the disease relevant to RAS system, including hypertension, heart disease etc..
Background technology
Renin angiotensin aldosterone system (RAAS) is a kind of regulating blood flow amount complicated, efficient, electrolyte balance And efficient system necessary to arteriotony.Two major parts of this system are feritin and angiotensin transferase. Feritin is a kind of aspartyl protease, and it can make to produce conversion of angiotensinogen angiotensinⅠ, vasotonia at liver Element I is at tonin (Angiotensin Converting EnzyCH3, ACE) effect under generate blood vessel tight Open element II, be finally translated into and can promote the AGT Ⅲ of Aldosterone Secretion and inactivate.AngiotensinⅡ is a kind of effect Extremely strong peptides vasoconstrictor also can promote that norepinephrine discharges from teleneuron, also by activating proto-oncogene c- Jun, c-fos, c-myc, egr-1 etc. express and promote vascular smooth muscle growth and cardiac structure reconstruct, produce in hypertension Important effect.
AngiotensinⅡ is the vasoconstrictor substance that a kind of effect is the strongest, and the effect of its liter of blood pressure is equivalent on nor-kidney 50 times of parathyrine.Angiotensin I-converting enzyme inhibitor (ACEI) and angiotensin ii receptor antagonist (ARB) can press down The generation of Angiotensin II processed, thus vasodilator effectively, reduce blood pressure, and is widely used to treat hypertension and be correlated with Disease.
ACEI and ARB all acts on RAAS, can not be used in combination in theory.But existing clinical observation finds ACEI and ARB Use in conjunction is more preferable to reducing urine protein effect, and randomized controlled trial also draws identical result.Val-Heft research in 93% Patient share ACEI, and result shows: valsartan all lowers with prevalence and the case fatality rate, again admission rate of ACEI use in conjunction, the heart The symptom that declines is improved more preferable than alone ACEI with LVEF.CHARM-Added tests for having taken ACEI (and beta-blocker) Chronic heart failure, add the danger 15% that can reduce cardiovascular death and hospitalization with Candesartan further.ARB and ACEI all can block the adverse effect of RAAS, and therapy mechanism is not quite similar, ACEI Yu ARB use in conjunction may produce collaborative work With, but whether be of universal significance and still leave a question open.The present inventor have surprisingly been discovered that one can act on RAAS system Double inhibitor, the risk of ACEI Yu ARB use in conjunction does not occur.
Summary of the invention
The present invention provides a kind of compound for renin angiotensin aldosterone system double inhibitor, can be used for Prevent or treat the disease relevant to RAAS system, including hypertension, congestive heart failure, pulmonary hypertension, renal function not Entirely, renal ischaemia, renal failure, renal fibrosis, Cardiac Insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiac muscle Disease, glomerulonephritis, renal colic, the diabetes the complication such as nephropathy, vascular lesion and neuropathy, green light that cause Postoperative concurrent of postoperative restenosis, blood vessel or the Cardiac surgical procedures of eye, intraocular pressure rising, atherosclerosis, vascularization Disease, erection disturbance, aldosteronism, lungs fibrosis, scleroderma, anxiety, cognitive disorder, controlling by immunosuppressant The disease that complication caused by treatment and other known with described renin-angiotensin system are associated.
One invention of the present invention, it is provided that the compound as shown in following formula (I), its stereoisomer, or it is pharmaceutically Acceptable salt:
Wherein,
R1Represent hydrogen or C1-6Alkyl, described C1-6Alkyl can be selected from hydroxyl, sulfydryl, amino, C1-6Alkyl oxy, C1-6The group of alkyl sulfenyl, amino carbonyl, guanidine radicals, indyl and imidazole radicals replaces；
R2Represent hydrogen, C1-6Alkyl, C3-6Cycloalkyl, C2-6Thiazolinyl or C2-6Alkynyl；
R3Represent hydrogen, C1-6Alkyl,Its Middle m represents 1,2 or 3, R31Represent hydrogen or C1-6Alkyl；
R4Represent acidic-group, preferably carboxyl, phosphate, sulfonic group or tetrazole radical；
R5Represent C1-6Alkyl-acyl；
R6Represent hydrogen or C1-6Alkyl, described C1-6Alkyl can be selected from hydroxyl, sulfydryl, amino, C1-6Alkyl oxy, C1-6The group of alkyl sulfenyl, amino carbonyl, guanidine radicals, indyl and imidazole radicals replaces；
X represents-NH-,-S-or-O-；
N is 0 or 1.
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, R1Represent methyl.
In a further preferred embodiment, R3Represent hydrogen, methyl, ethyl,
In a further preferred embodiment, R4Represent tetrazole radical.
In a further preferred embodiment, R5Represent valeryl.
In a further preferred embodiment, R6Represent isopropyl.
The present invention also provides for a kind of pharmaceutical composition, and it includes the compounds of this invention as shown in formula (I) and pharmaceutically may be used The carrier accepted or excipient.
Described medicine can be used for prevention or treats the disease being associated with renin-angiotensin system, described disease Selected from hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischaemia, renal failure, renal fibrosis, the heart Dirty insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, caused by diabetes Complication such as nephropathy, vascular lesion and neuropathy, glaucoma, intraocular pressure rising, atherosclerosis, vascularization The postoperative complication of postoperative restenosis, blood vessel or Cardiac surgical procedures, erection disturbance, aldosteronism, lungs are fine Dimensionization, scleroderma, anxiety, cognitive disorder, by the complication caused by the treatment of immunosuppressant and other are known and described The disease that is associated of renin-angiotensin system.
Unless stated otherwise, used herein above to " alkyl " being intended to includes having the carbon number purpose side chain specified or straight The saturated fat hydrocarbyl group of chain.Such as, " C1-6Alkyl " or " C1-C6Alkyl " represent have appointment carbon number purpose linear or The alkyl group of person's side chain, including all of isomer.C1-6The example of alkyl includes methyl, ethyl, n-pro-pyl, isopropyl, just Butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, n-hexyl etc..
Similarly, " cycloalkyl " is intended to include having the carbon number purpose ring-type saturated fat hydrocarbyl group specified.Such as, “C3-6Cycloalkyl " or " C3-C6Cycloalkyl " represent to have and specify carbon number purpose cyclic alkyl radical, including all of different Structure body.C3-6The example of alkyl includes ring n-pro-pyl, cyclobutyl, cyclopenta, cyclohexyl etc..
The salt of the compound of the present invention includes pharmaceutically acceptable salt class, including the salt formed with mineral acid, such as salt Acid, hydrobromic acid, sulphuric acid, sulfonic acid, phosphoric acid, nitric acid and class acidoid；With organic acid addition salt, including acetate, adipate, algae Hydrochlorate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, Camphora hydrochlorate, camphorsulfonic acid Salt, cyclopentane propionate, double gluconate, lauryl sulfate, ethyl sulfonate, fumarate, glucose enanthic acid Salt, glycerophosphate, Hemisulphate, enanthate, caproate, hydrochlorate, hydrobromate, hydriodate, 2-hydroxyethylsulfonic Salt, lactate, maleate, metilsulfate, 2-naphthyl sulphonic acids salt, nicotinate, nitrate, oxalates, embonate, really Glue hydrochlorate, persulfate, 3-phenylpropionic acid salt, picrate, pivalate, propionate, succinate, sulfate, tartaric acid Salt, rhodanate, toluene fulfonate and undecylate；The most inorganic or organic acid or the quaternary ammonium salts of alkali；Soda acid formula Salt includes what ammonium salt, alkali metal salt such as sodium salt and potassium salt, alkali salt such as calcium salt and magnesium salt and organic base were formed Salt such as hexanamine salt, N-methyl-D-glucarnine, and with amino acids formed salt such as arginine, lysine, etc. Deng.Same, described Basic nitrogen-containing groups can, such as methyl, second quaternary ammoniated by the such as such reagent of lower halogenated alkane Base, propyl group and butyl chloride, bromine and iodine；Dialkyl sulfate such as dimethyl, diethyl, dibutyl；And diamyl sulfur Hydrochlorate, long chain halide such as undecyl, dodecyl, myristyl and octadecyl chloride, bromine and iodine, aryl alkyl Halogenide such as benzyl and phenethyl bromide and other.
General preparative methods
The compound of the present invention can use following general preparative methods to obtain, and described method includes:
Formula (II) compound is made to contact with formula (III) compound to obtain formula (I) compound；
Formula (III) compound can be condensed into the proline derivative shown in formula (VIII) by the acyl chlorides shown in formula (VII) Formula (VI) compound, is then converted into the acyl chlorides shown in formula (V), then is condensed with the alcohol shown in formula (IV) and obtains.
Then formula (II) compound can be acylated by the bromo-derivative shown in formula (IX) and formula (X) compound condensation and obtained:
In formula, substituent group is as hereinbefore defined.Alternatively, above-mentioned formula (II)～(XI) compound equal portability protective agent, close It is well known in the art in the suitable example of protection group.
Specific embodiment
The preparation of formula (II) compound
1.N-valeryl-N-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L-valyl The preparation of chlorine (intermediate 1)
Step 1, the system of N-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L-Valine Standby
In 250mL there-necked flask, add potassium carbonate (12.5g) and acetonitrile (85mL), add Valine (5.0g), stir Mix, react 0.5h；Add 2-N-trityl-5-(4'-bromomethylbiphenyl-2-base) tetrazole (16.7g), be heated to backflow anti- Answer 8h, be cooled to room temperature, filter, wash filter cake with 10mL acetonitrile；Merging filtrate, vacuum rotary steam, recycling design.Residue adds Enter 100mL ethyl acetate, ethyl acetate layer salt washing (30mL × 2).Ethyl acetate layer anhydrous sodium sulfate filters after drying, returns Receive solvent, obtain title compound.Molecular formula: C38H35N5O2, mass spectral analysis (m/z): m/z:593.28 (100.0%), 594.28 (43.0%).Elementary analysis: C, 76.87；H,5.94；N,11.80；O,5.39.
Step 2, N-valeryl-N-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L-figured silk fabrics The preparation of propylhomoserin
Step 1 products therefrom is dissolved in toluene (100mL), adds sodium bicarbonate (4.1g), stir 0.5h.It is cooled to 5 DEG C, dropping valeric chloride (4.6mL).30h is stirred at room temperature after adding.After having reacted, add 10% sodium bicarbonate solution (30ml), 4h is stirred at room temperature.Layering, toluene layer salt washing (30mL × 2), anhydrous sodium sulfate filters after drying, and recycling design obtains titled Compound.Molecular formula: C43H43N5O3, mass spectral analysis (m/z): 677.34 (100.0%), 678.34 (47.1%).
Elementary analysis: C, 76.19；H,6.39；N,10.33；O,7.08.
Step 3, N-valeryl-N-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L-figured silk fabrics The preparation of aminoacyl chlorine
The product (8.9mmoL) of step 2 is joined in four-hole boiling flask, is stirred at room temperature down and slowly drips the two of equimolar amounts Chlorine sulfoxide, absorbs, with sodium hydroxide or potassium hydroxide solution, the gas produced.It is warming up to 70 DEG C after being added dropwise to complete, continues stirring Reaction 6h.Decompression distillation, obtains title compound.Molecular formula: C43H42N5O2Cl, mass spectral analysis (m/z): 6695.30 (100.0%), 696.31 (47.1%), 697.30 (32.8%).
Elementary analysis: C, 74.17；H,6.08；Cl,5.09；N,10.06；O,4.60.
2.N-valeryl-N-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L-leucyl The preparation of chlorine (intermediate 2)
Step 1, the system of N-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L-leucine Standby
In 250mL there-necked flask, add potassium carbonate (12.5g) and acetonitrile (85mL), add L-Leu (5.6g), stir Mix, react 1h；Add 2-N-trityl-5-(4'-bromomethylbiphenyl-2-base) tetrazole (16.7g), be heated to back flow reaction 8h, is cooled to room temperature, filters, and washs filter cake with 10mL acetonitrile；Merging filtrate, vacuum rotary steam, recycling design.Residue adds 100mL ethyl acetate, ethyl acetate layer salt washing (30mL × 2).Ethyl acetate layer anhydrous sodium sulfate filters after drying, reclaims Solvent, obtains title compound.Molecular formula: C39H37N5O2；Mass spectral analysis (m/z): 607.29 (100.0%), 608.30 (42.7%)；Elementary analysis: C, 77.07；H,6.14；N,11.52；O,5.26.
Step 2, N-valeryl-N-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L-are bright The preparation of propylhomoserin
Step 1 products therefrom is dissolved in toluene (100mL), adds sodium bicarbonate (4.1g), stir 0.5h.It is cooled to 5 DEG C, dropping valeric chloride (4.6mL).30h is stirred at room temperature after adding.After having reacted, add 10% sodium bicarbonate solution (30ml), 4h is stirred at room temperature.Layering, toluene layer salt washing (30mL × 2), anhydrous sodium sulfate filters after drying, and recycling design obtains titled Compound.Molecular formula: C44H45N5O3；Mass spectral analysis (m/z): 691.35 (100.0%), 692.36 (48.2%)；Elementary analysis: C, 76.38；H,6.56；N,10.12；O,6.94.
Step 3, N-valeryl-N-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L-are bright The preparation of aminoacyl chlorine
The product (9.0mmoL) of step 2 is joined in four-hole boiling flask, is stirred at room temperature down and slowly drips the two of equimolar amounts Chlorine sulfoxide, absorbs, with sodium hydroxide or potassium hydroxide solution, the gas produced.It is warming up to 65 DEG C after being added dropwise to complete, continues stirring Reaction 7h.Decompression distillation, obtains title compound.Molecular formula: C44H44ClN5O2；Mass spectral analysis (m/z): 709.32 (100.0%), 710.32 (50.0%)；Elementary analysis: C, 74.40；H,6.24；Cl,4.99；N,9.86；O,4.50.
3.N-valeryl-N-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L-seryl The preparation of chlorine (intermediate 3)
Step 1, the system of N-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L-serine Standby
In 250mL there-necked flask, add potassium carbonate (12.5g) and acetonitrile (85mL), add Serine (4.5g), stir Mix, react 1h；Add 2-N-trityl-5-(4'-bromomethylbiphenyl-2-base) tetrazole (16.7g), be heated to back flow reaction 8h, is cooled to room temperature, filters, and washs filter cake with 15mL acetonitrile；Merging filtrate, vacuum rotary steam, recycling design.Residue adds 100mL ethyl acetate, ethyl acetate layer salt washing (30mL × 2).Ethyl acetate layer anhydrous sodium sulfate filters after drying, reclaims Solvent, obtains title compound.Molecular formula: C36H31N5O3；Mass spectral analysis (m/z): 581.24 (100.0%), 582.25 (39.4%)；Elementary analysis: C, 74.34；H,5.37；N,12.04；O,8.25.
Step 2, N-valeryl-N-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L-silk The preparation of propylhomoserin
Step 1 products therefrom is dissolved in toluene (100mL), adds sodium bicarbonate (4.1g), stir 0.5h.It is cooled to 5 DEG C, dropping valeric chloride (4.6mL).30h is stirred at room temperature after adding.After having reacted, add 10% sodium bicarbonate solution (30ml), 4h is stirred at room temperature.Layering, toluene layer salt washing (30mL × 2), anhydrous sodium sulfate filters after drying, and recycling design obtains titled Compound.Molecular formula: C41H39N5O4；Mass spectral analysis (m/z): 665.30 (100.0%), 666.30 (46.3%)；Elementary analysis: C, 73.96；H,5.90；N,10.52；O,9.61.
Step 3, N-valeryl-N-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L-silk The preparation of aminoacyl chlorine
The product (8.9mmoL) of step 2 is joined in four-hole boiling flask, is stirred at room temperature down and slowly drips the two of equimolar amounts Chlorine sulfoxide, absorbs, with sodium hydroxide or potassium hydroxide solution, the gas produced.It is warming up to 65 DEG C after being added dropwise to complete, continues stirring Reaction 7h.Decompression distillation, obtains title compound.Molecular formula: C41H38ClN5O3；Mass spectral analysis (m/z): 683.27 (100.0%), 684.27 (44.9%)；Elementary analysis: C, 71.97；H,5.60；Cl,5.18；N,10.24；O,7.01.
4.N2-valeryl-N2-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L-paddy ammonia The preparation of amide acyl chlorides (intermediate 4)
Step 1, N2-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L-glutaminate Preparation
In 250mL there-necked flask, add potassium carbonate (12.5g) and acetonitrile (85mL), add L-glutaminate (6.2g), Stirring, reacts 1h；Add 2-N-trityl-5-(4'-bromomethylbiphenyl-2-base) tetrazole (16.7g), be heated to backflow anti- Answer 8h, be cooled to room temperature, filter, wash filter cake with 15mL acetonitrile；Merging filtrate, vacuum rotary steam, recycling design.Residue adds Enter 100mL ethyl acetate, ethyl acetate layer salt washing (30mL × 2).Ethyl acetate layer anhydrous sodium sulfate filters after drying, returns Receive solvent, obtain title compound.Molecular formula: C38H34N6O3；Mass spectral analysis (m/z): 622.27 (100.0%), 623.27 (43.4%)；Elementary analysis: C, 73.29；H,5.50；N,13.50；O,7.71.
Step 2, N2-valeryl-N2-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L- The preparation of glutamine
Step 1 products therefrom is dissolved in toluene (100mL), adds sodium bicarbonate (4.1g), stir 0.5h.It is cooled to 5 DEG C, dropping valeric chloride (4.6mL).30h is stirred at room temperature after adding.After having reacted, add 10% sodium bicarbonate solution (30ml), 4h is stirred at room temperature.Layering, toluene layer salt washing (30mL × 2), anhydrous sodium sulfate filters after drying, and recycling design obtains titled Compound.Molecular formula: C43H42N6O4；Mass spectral analysis (m/z): 706.33 (100.0%), 707.33 (47.1%)；Elementary analysis: C, 73.07；H,5.99；N,11.89；O,9.05.
Step 3, N2-valeryl-N2-(4-(2-(1-trityl-1H-tetrazole-5-base) phenyl) phenyl) methyl-L- The preparation of glutamine acyl chlorides
The product (8.9mmoL) of step 2 is joined in four-hole boiling flask, is stirred at room temperature down and slowly drips the two of equimolar amounts Chlorine sulfoxide, absorbs, with sodium hydroxide or potassium hydroxide solution, the gas produced.It is warming up to 65 DEG C after being added dropwise to complete, continues stirring Reaction 7h.Decompression distillation, obtains title compound.Molecular formula: C43H41ClN6O3；Mass spectral analysis (m/z): 724.29 (100.0%), 725.30 (47.1%), 726.29 (33.0%)；Elementary analysis: C, 71.21；H,5.70；Cl,4.89；N,11.59；O,6.62.
The preparation of formula (III) compound
5. the preparation of ((S)-3-sulfydryl-2-methylpropionyl)-L-PROLINE methyl ester (intermediate 5)
L-PROLINE (2.8mmol), the NaOH solution (2.8mmol) of 8%, stirring and dissolving, temperature is added in four-hole boiling flask Degree is reduced to 0 DEG C, starts to drip (S)-3-sulfydryl-2-methyl-prop acyl chlorides (3.5mmol), maintains by the NaOH solution of 8% simultaneously The pH of reaction system is at 7.5-9, and temperature is maintained at 0-5 DEG C, after acyl chlorides drips, continues the NaOH solution of dropping 8%, and regulation is anti- The pH answering system is 7, till constant.Reaction 3 hour is stirred at room temperature, is then neutralized with hydrochloric acid under low temperature, then uses acetic acid Ethyl ester extractive reaction liquid, merges organic facies, and the NaCl solution with 10% is washed, anhydrous MgSO4It is dried, is filtered to remove desiccant. Recycling design obtains title compound.Molecular formula: C9H15NO3S；Mass spectral analysis (m/z): 217.08 (100.0%)；Elementary analysis: C,49.75；H,6.96；N,6.45；O,22.09；S,14.75
The preparation of 6.L-alanyl-L-PROLINE (intermediate 6)
Replacing (S)-3-sulfydryl-2-methyl-prop acyl chlorides with L-alanyl chloride, the method for intermediate 5 is prepared in enforcement, it is thus achieved that L- Alanyl-L-PROLINE.Molecular formula: C8H14N2O3；Mass spectral analysis (m/z): 186.20 (100.0%)；Elementary analysis: C, 51.60；H,7.58；N,15.04；O,25.78
The preparation of 7.L-alanyl-L-PROLINE 2,3-dinitro epoxide glyceride (intermediate 7)
The ethyl acetate solution of intermediate 6 is joined in four-hole boiling flask, is stirred at room temperature down and slowly drips equimolar amounts Thionyl chloride, is warming up to 60 DEG C after being added dropwise to complete, continue stirring reaction 5h, and decompression distillation is with recycling design.Product is dissolved in DMF In, add potassium carbonate, stirring and dissolving, be subsequently adding (3aS, 6aR)-6-hydroxyl-hexahydro furyl also [3,2-b] furan-3-nitric acid Ester, stirs mixture 2 hours at 70 DEG C.After having reacted, it is added thereto to water, extracts by ethyl acetate, silica gel column layer Analysis separates, and obtains product.Molecular formula: C14H21N3O8Mass spectral analysis (m/z): 359.13 (100.0%)；Elementary analysis: C, 46.80； H,5.89；N,11.69；O,35.62.
It is likewise possible to prepare intermediate 8-14 (seeing table 1).
Table 1
Formula(I) preparation of compound
Embodiment 1
(3-((N-(4-(2-(1H-tetrazole-5-base) phenyl) phenyl) methyl)-N-valeryl-L-is valyl) sulfur Base)-2-methylpropionyl) preparation of-L-PROLINE (compound 1)
In four-hole boiling flask, add intermediate 5 (3.0mmol), potassium carbonate (3.0mmol) and DMF (100ml), stir molten Solving, temperature is reduced to 0 DEG C, starts to drip intermediate 1 (3.0mmol), maintains the pH of reaction system to exist with solution of potassium carbonate simultaneously 7.0-8.0, temperature is maintained at 0 DEG C, after being added dropwise to complete, continues dropping solution of potassium carbonate, and the pH of regulation reaction system is 7, until Till constant.Reaction 3 hour is stirred at room temperature, is then added thereto to water (40ml), extract by ethyl acetate, recycling design.Surplus Excess silica gel adsorption, n-hexane/acetone eluting, obtain title compound.
Molecular formula: C33H42N6O5S, mass spectral analysis (m/z): 634.29 (100.0%), 635.30 (36.4%).
Elementary analysis: C, 62.44；H,6.67；N,13.24；O,12.60；S,5.05.
1H NMR (6d-DMSO): 12.22 (1H), 7.96 (2H), 7.60 (2H), 7.41-7.47 (4H), 6.33 (1H), 4.46 (2H), 4.33 (1H), 4.26 (1H), 3.41-3.51 (1H), 2.96-3.21 (2H), 2.65-2.73 (2H), 2.02- 2.33 (6H), 1.53 (2H), 1.38 (2H), 1.17 (3H), 0.93-0.96 (9H)
Embodiment 2
(3aR, 6aS)-3-(N-((2'-(1H-TETRAZOLE-5-base)-[1,1'-biphenyl]-4-base) methyl) the positive valeryl of-N-- L-leucyl--L-alanyl-L-prolyl epoxide)-6-(nitre epoxide) hexahydro furyl also [3,2-b] furan (compound 2) Preparation
With the similar method of embodiment 1, intermediate 2 and intermediate 7 is made to react in the presence of the alkaline reagents such as potassium carbonate, Title compound.Molecular formula: C39H50N8O10；Mass spectral analysis (m/z): 790.36 (100.0%), 791.37 (43.1%)；Element Analyze: C, 59.23；H,6.37；N,14.17；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)。
Embodiment 3
(3aR, 6aS)-3-(N-((2'-(1H-TETRAZOLE-5-base)-[1,1'-biphenyl]-4-base) methyl) the positive valeryl of-N-- L-seryl--L-alanyl-L-prolyl epoxide)-6-(nitre epoxide) hexahydro furyl also [3,2-b] furan (compound 3) Preparation
With the similar method of embodiment 1, intermediate 3 and intermediate 7 is made to react in the presence of the alkaline reagents such as potassium carbonate, Title compound.Molecular formula: C36H44N8O11；Mass spectral analysis (m/z): 764.31 (100.0%), 765.32 (39.9%)；Element Analyze: C, 56.54；H,5.80；N,14.65；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)。
Embodiment 4
(3aR, 6aS)-3-(N2-((2'-(1H-TETRAZOLE-5-base)-[1,1'-biphenyl]-4-base) methyl) positive valeryl of-N2- Base-L-glutaminate acyl group-L-alanyl-L-prolyl epoxide) (the change of-6-(nitre epoxide) hexahydro furyl also [3,2-b] furan Compound 4) preparation
With the similar method of embodiment 1, intermediate 4 and intermediate 7 is made to react in the presence of the alkaline reagents such as potassium carbonate, Title compound.Molecular formula: C38H47N9O11；Mass spectral analysis (m/z): 805.34 (100.0%), 806.34 (44.8%)；Element Analyze: C, 56.64；H,5.88；N,15.64；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)。
Similarly, react in the presence of the alkaline reagents such as potassium carbonate with intermediate 1-4 respectively with intermediate 5-14, can make The standby following compound (seeing table 2) that obtains:
Table 2
Application Example
1, the test of angiotensin-ii receptor antagonistic activity
According to (determination of activity of Angiotensin Ⅱ receptor antagonist, " journal of Beijing Medical University " 1998 such as Wang Xiaowei Volume 30 the 4th phase in the end of the year, page 370) disclosed in method test.
About 100 μ g liver memebrane proteins, fixed amount is added in 0.35ml rat liver cell membrane receptor response liquid125I-blood vessel The cold angiotensin-ii-receptor that Angiotensin Ⅱ receptor (about 5,000 counting rate/min) and 0.045ng to 30ng do not wait, Non-specific pipe adds 1 μ g angiotensin-ii-receptor, reacts 70min at 25 DEG C, and water-bath terminates reaction, and bull catcher will be in conjunction with 's125I-angiotensin-ii-receptor is collected in glass fiber filter paper (with 1mg/L angiotensin-ii-receptor presaturation), Each every effective 5ml flushing liquor, washes 3～4 times altogether.Gamma counter measures radioactivity, calculates IC50Value.
Test result indicate that, the IC of above-described embodiment compound 1-4050≤2μmol。
2, Angiotensin-Converting I inhibition test
According to (assay method of angiotensin-convertion enzyme inhibitor suppression ratio, " food science and technologies " 2007 years such as Shen Yaolin 3rd phase the 212-216 page) disclosed in HPLC-ESI-MS method test.Result shows, above-described embodiment compound 1-40's IC50≤1μmol。
3, active nitrogen free radical (RNS) detection (diaminonaphthalene detection)
The method proposed according to Kostka and Park (sees CH3Thods Enzymol. " Enzymology method " 1999, 301,227-235), high performance liquid chromatography (HPLC) fluorescence detection is utilized, process through ethylenediaminetetraacetic acid (EDTA) The blood plasma of rat detects the active nitrogen free radical (RNS) of S-nitrosothiol form.Described method is with fluorescence 2,3-naphthols Based on the detection of triazole (NAT), described fluorescence 2,3-naphthols triazole is logical superacidulated 2,3-diaminonaphthalene (DAN) with And the reaction that occurs between nitrous half race of described nitrosothiols (RSNOs) and produce, wherein said nitrosothiols Nitrous half race be the fracture of the S-NO key mediated by mercuric chloride and discharge.Utilize reversed-phase high-performance liquid chromatography to described instead Answer mixed liquor to carry out chromatographed, and the fluorescence signal at naphthols triazole (NAT) peak parsed is quantified.
First in undressed black polypropylene titer plate, with the ratios with water (20 microlitre) of 1:1, to blood plasma, (20 is micro- Rise) it is diluted.(every hole 100 microlitre is present in 0.1N hydrochloric acid, 4 mmoles mercuric chloride to add diaminonaphthalene (DAN) reagent 100 micro-diaminonaphthalenes that rub), and use opaque backing plate that described titer plate is sealed immediately, rotate, and black Cultivate 10 minutes in the dark.Described plate it is centrifuged (2000x g, 5 minutes) and is cooled to 4 DEG C, carrying out efficient liquid phase afterwards Chromatograph (HPLC) is analyzed.The automatic sampler (4 DEG C) utilizing cooling in Agilent 1200 system carries out high performance liquid chromatography (HPLC).Sample carries out chromatograph reaction in C8 post (Zorbax Eclipse XDB-C8,4.6x 150 millimeters, 5 microns), profit With the methanol of 67%, the ammonium acetate of 0.1% as flowing phase, carry out isocratic elution with the flow velocity of 2 ml/min.Utilize 360 The excitation wavelength of nanometer monitors the fluorescence of naphthols triazole in 450 nanometers.Sodium nitrite is utilized to prepare school in comparison blood plasma Directrix curve.
The active nitrogen Free Radical Level of the above embodiment of the present invention compound 1-40 peaked in about 1 hour, logical It is often 0.1 to 30 micro-to rub, thus confirms that the nitre oxo-compound of the present invention generates nitric oxide in vivo, thus to being used Test-compound produces response.
4, drop test
The ability of the compounds of this invention blood pressure lowering is evaluated in conscious spontaneous hypertensive rat (SHRs).Continuous 3 Day gives control compound or the compounds of this invention of each group of SHRs (250-300g) equimolar dosage.After administration, pass through long distance The systolic blood pressure (SBP) of algoscopy monitoring different time points and Heartbeat rate.Result is as shown in table 3 below:
Table 3: the impact (mmHg) of compounds on shrinkage phase blood pressure
Compound Basic blood pressure 30min 12h 24h
Compound 1 145 123 123 123
Compound 2 145 125 126 127
Compound 3 145 125 126 126
Compound 4 145 122 123 123
Control compound 1 145 132 135 135
Control compound 2 145 135 136 137
Control compound 3 145 113 128 130
Note: control compound 1 is valsartan potassium, control compound 2 is captopril, and control compound 3 is 2-butyl-4- Chloro-1-((2'-(1H-tetrazole-5-base) biphenyl-4-base) methyl)-1H-imidazole-5-carboxylic acid-1-(((2-(2,3-bis-(nitre oxygen Base) propoxyl group) ethyoxyl) carbonyl) epoxide) ethyl ester.
Experiment shows, the compound 1-40 of the present invention all shows above-mentioned similar blood pressure lowering character.Compared with the control, whole During individual treatment, compared with control compound 1-3, the compound 1-40 of the present invention all shows and continues and strongly reduce blood pressure To the ability of normal level, and it is not result in blood pressure fluctuation, it is to avoid the generation of severe hypotension.

Claims (10)

1. compound as shown in following formula (I), its stereoisomer, or its pharmaceutically acceptable salt:
Wherein,
R1Represent hydrogen or C1-6Alkyl, described C1-6Alkyl can be selected from the group of sulfydryl and amino and replace；
R2Represent hydrogen or C1-6Alkyl；
R3Represent hydrogen, C1-6Alkyl,Wherein m generation Table 1, R31Represent hydrogen；
R4Represent tetrazole radical；
R5Represent valeryl；
R6Represent hydrogen or C1-6Alkyl, described C1-6Alkyl can be selected from hydroxyl and aminocarboxy group replaces；
X represents-NH-or-S-；
N is 0 or 1.
Compound the most according to claim 1, it is characterised in that X represents NH, and n is 0.
Compound the most according to claim 1, it is characterised in that X represents S, and n is 1.
4. according to the compound described in any one of claim 1-3, it is characterised in that R1Represent methyl.
5. according to the compound described in any one of claim 1-3, it is characterised in that R3Represent hydrogen, methyl, ethyl,
6. according to the compound described in any one of claim 1-3, it is characterised in that R6Represent isopropyl.
7. compound, is selected from:
8. a pharmaceutical composition, it includes according to the compound described in any one of claim 1-7.
9., according to the application in preparing medicine of the compound described in any one of claim 1-7, described medicine is used for preventing Or the disease that treatment is associated with renin-angiotensin system.
Application the most according to claim 9, described disease is selected from hypertension, congestive heart failure, pulmonary artery height Pressure, renal insufficiency, renal ischaemia, renal failure, renal fibrosis, Cardiac Insufficiency, cardiac hypertrophy, cardiac fibrosis, the heart The postoperative restenosis of the rising of myocardial ischemia, glomerulonephritis, renal colic, glaucoma, intraocular pressure, atherosclerosis, vascularization, Blood vessel or the postoperative complication of Cardiac surgical procedures, erection disturbance, aldosteronism, lungs fibrosis, scleroderma, Jiao Worry, cognitive disorder.
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