GB2589531A - A new renin inhibitor - Google Patents

Abstract

A compound of formula I or a pharmaceutically acceptable salt thereof: I wherein R is hydrogen; R1 is C1-C4 alkyl; phenyl or substituted phenyl; hydrogen atom; wherein substituent group of the substituted phenyl in R1 is: methyl; ethyl; propyl; amino; nitro; halogen, wherein the halogen is fluorine, chlorine, bromine or iodine; R2 is C1-C4 alkyl; phenyl or substituted phenyl; hydrogen; wherein substituent group of the substituted phenyl in R2 is: methyl; ethyl; propyl; amino; nitro; halogen, wherein the halogen is fluorine, chlorine, bromine and iodine; R3 is hydrogen; C1-C6 alkyl; C3-C6 cycloalkyl; benzyl. Preferably, R1 is hydrogen, methyl or ethyl; R2 is methyl, phenyl, ethyl, benzyl, 2-naphthyl or 2-aminophenyl; R3 is methyl, cyclohexyl, benzyl or ethyl. These compounds have a substituted pyrrolidine-3-carboxylic acid-3-dimepiperate structure and are renin inhibitors, which can be used in diseases related to blocking the renin-angiotensin system (RAS), including hypertension, cardiovascular disease and so on.

Description

A NEW RENIN INHIBITOR

TECHNICAL FIELD

[0001] The present invention relates to a new renin inhibitor, in particular refer to Pyrrolidine-3-carboxylic acid-3-dimepiperate, a preparation method, especially a function as a reinin inhibitor,

BACKGROUND OF THE INVENTION

[0002] A chromic persistent activation of RAAS is an important factor in causing and developing cardiovascular disease, kidney disease and diabetes. Therefore, RAAS has became the main physiopathologic target in intervening the above diseases. Three aspects can be began to block a physiopathologic function of RAAS: ACEI reduce a conversion of angiotensinogen to angiotensin I(AngI); ARE block a function of the angiotensin II(AngII); renin inhibitor block RAAS from an origin to effectively reduce a generation of AngI and Angll. According to previous studies, ACE or ARB block RAAS, which can cause an increasing in compensatory of renin activity in plasma and an accumulation of the AngI, vice verse, Angiotensin II escape was observed when RAAS is activated. Moreover, a renin inhibiting can block and lower an activity of the whole RAAS, which is able to become a reasonable treatment measure with benefit potentially.

[0003] Renin is a kind of Aspartic acid proteinase, mainly synthesized by kidney juxtaglomerular cells with a species specificity. Firstly, prorenin without biological activity is synthesized by the kidney juxtaglomerular cells, and then the prorenin is processed in cells, and then the prorenin convert into single chain active renin after a plurality of amino acid are removed, and the single chain active renin is stored in secretory granules; when an external stimulus present, the single chain active renin is released into blood or tissues; a chronic activation of RAAS accelerate a conversion from prorenin to renin. A releasing of renin is influenced by the following factors: hypotension, hyponatremia or a reduction of body volume will stimulate the kidney juxtaglomerular cells to release the renin; an excitation of kidney sympathetic nerves(with kidney f3lreceptor-mediated) increases a releasing of renin; the angiotensin II(AngII) inhibits a releasing of renin by a negative feedback of AT receptors. Previous studies think that the renin only has a function of generating AngI by catalyzing a hydrolysis of the angiotensinogen; however, with a discovery of the renin receptor, people realized that, except a performance in enzymatic activity with a free form to promote a creation of the angiotensin, the renin can also trigger a conductive path for new signals which differ from receptor signals of the angiotensin II(AngII); after the renin bind to the renin receptor, the ability to catalyze the angiotensinogen to hydrolyze to generate AngI has been significantly improved. In recent years, studies shows that the prorenin without activity can also bind to renin receptor for a configuration changing, which has the same enzymatic activity as the renin. Therefore, the renin receptor has been changed name to prorenin/ renin receptor. The prorenin/renin receptors are widely distributed in kidney, heart, liver, pancreas, placenta, retina, vascular smooth muscle cell and other tissues. The prorenin bind to the prorenin/renin receptor to stimulate a phosphorylation to Kinase ERK I (p44)*I1 ERK2(p42) of Mitogen-activated Protein(MAP), an up-regulation expression of pro-fibrotic moleculars like Transforming growth factorRTGF-f3), Plasminogen activator i1nhibitor-l(PAI-1) and fibronectin, an excitement on pathways of p38MAP kinase / Heat shock protein 27, thus caused the changes of actin dynamics. The activation of the renin receptor independent of Angll mechanism can lead to a tissue fibrosis and a cell hypertrophy, which may causes cardiovascular and renal diseases. In recent years, the ACEI and the ARB that effectively block the RAAS have been widely applied in hypertension, coronary heart disease, myocardial infarction(M1), Diabetic Nephropathy(DN), Deficient systolic heart failure anf other diseases. However, after a treatment of ACEI or ARB, due to the negative feedback, the activity of the renin has been dramatically increased, and then the angiotensin II(AngII) and the aldosterone escape may be occur. Treatments with ACEI and ARB are managed to be combined to comprehensively strengthen a blocking of RAAS, but there is no obvious clinical effect. The renin is a protease for initiating and rate-limiting of the RAAS, and the renin activity is a key point to regulate the whole RAAS state, which performs a function to adjust the blood pressure and cardiovascular efficiency. A direct inhibition to the renin activity can offset an increasing of compensatory renin activity caused by the ACEI or the ARB, which also rarely intervene other physiological methods to reach a comprehensive strengthening of blocking the RAAS.

[0004] Although the No.06/069788 International Application discloses that 3,4-substituted piperidine compound is used to prepare the renin inhibitor. However, there are no detailed description on Pyrrolidine-3-carboxylic acid-3-dimepiperate compound in this published patent.

BRIEF SUMMARY OF THE INVENTION

[0005] This invention provides a new compound with an excellent renin inhibiting function.

[0006] This invention refers to a new renin inhibitor, especially refer to derivatives of Substituted Pyrrolidine-3-carboxylic acid-3-dimepiperate, or a pharmaceutically acceptable salt in formula I In the formula R can denote 1) Hydrogen atom, 2) CI-Co alkyl group: 3) CI-C6 kenyl, 4) Ci-Co cycloalkyl; 5) phenyl or substituted phenyl; 6) benzyi or substituted benzykpyridyl or substituted pyridyl; 8) quinolyl or substituted quinoly1; 9) indolyl or substituted indolyl.

RI can denote: I) a straight chain CI-C4 alkylene; 2) phenyl or substituted phenyl; 3) pyridyl or substituted pyridyl; 4) pyrazoly1 or substituted pyrazoly1; 5) indolyl or substituted indolvl; 6) benzofirryi or substituted benzofuryl; 7) quinolyi or substituted quinoly1; 8) benzodihydropyranyl or substituted benzodihydropyrativ1; 9) dihydrobenzoluranyl or substituted dihydrobenzofuranyl; 10) indazolyl or substituted indazolyi; 11) pyrrolopyridinyl or substituted pyrrolopyridinyl; 12) benzisoxazoleyi or substituted hydrochlorideyl, 13) indolin-yl or substituted indolinyi; 14) quinazolinyl or substituted quinazolinyl; 15) dihydroquinazolinyl or substituted dihydro-quinazollnyl; 16) faro pyridvl or substituted furo pyridyl; 17) isoquinolyi or substituted isoquindly4; 18) pyrrol opyrimidinyl or substituted pyrrol opyi di mil; 19) tetrahydroquif101inyl or substituted tetrahydroqui nolinyl; 20) tetrahydroindazolyl or substituted tetrahydroindazobyt; 21) tetrahydrocyclo-penta pyrazolyi or substituted tetrahydrocyclo-penta pyrazob4; 22) substituted pyrrolyl; 23) imidazolyl or substituted imidazoly1; 24) pyrazolyl or substituted pyrazolyl; 25) pyrrolyi or substituted thienyl, 26) thiazolyl or substituted thiazolyl; 27) triazolyl; 28) pyrimidinyl; 29) pyrazinyl or substituted pyrazinyl; 30) imidazo pyridinor substituted imidazo pyridinor; 31) pyrrole pyrazinyl; 32) hydrogen atom.

[0007] the substitute group can be selected one or two identical or di)M following 1 [0008] 1) methyl; 2) ethyl; 3) propyl; 4) alkoxy; 5) acyl; 6) cyano; 7) ester groups 8) cycloalkyl; 9) amino groups; 10) sulfonyl; 11) nitro group; 12) halogen.

Wherein the halogen is fluorine, chlorine, bromine and iodine.

[0009] R2 can denote 1) a straight chain C-C4 alkylene; 2) phenyl or substituted phenyl; 3) pyridyl or substituted pyridyl; 4) pyrazolyl or substituted pyrazoly1; 5) indolyl or substituted indoly1; 6) benzoluryl or substituted benzofuryl; 7) quinoly1 or substituted quinolyi; 8) benzodihydropyranyl or substituted benzodihydropyranyl; 9) dihydrobenzofuranyl or substituted dihydrobenzofitranyl; 10) indazolyi or substituted indazolyi; 11) pyrrolopyridinyl or substituted pyrrolopyridinyl, 12) benzi soxazol eyi or substituted hydrochloridey1; 13) indolinyl or substituted indolinyl; 14) quinazolinyl or substituted quinazolinyl; 15) dihydro(luinazolinyl or substituted di hydro-quinazolinyl; 16) furo pyridyl or substituted furo pyridyl; 17) isoquinolyl or substituted isoquinolyl; 18) pyrrolopyrimiditayl or substituted pyrrolopyrimidinyi; 19) tetrahydroquinolinyl or substituted tetrahydroquinolinyl; 20) tetrahydroindazoly1 or substituted tetrahydroindazoly1; 21) tetrahydrocyclo-penta pyrazolyl or substituted tetrahydrocyclo-penta pyrazolyl; 22) substituted pyrroly1; 23) imidazolyl or substituted imidazolyl; 24) pyrazolyl or substituted pyrazolyl; 25) pyrroly1 or substituted thienyl; 26) thiazolyl or substituted thiazolyl; 27) triazolyl; 28) pyrimidinyt; 29) pyrazinyl or substituted pyrazinyt; 30) imidazo pyridinor substituted imidazo pyridinor; 3 pyrrole pyrazinyl; 32) hydrogen atom.

[0010] the substitute group can be selected one or tit. o identical or different groups from following 1)42): [0011] 1) methyl; 2) ethyl; 3) propyl; 4) alkoxy; 5) acyl; 6) cyano; 7) ester groups; 8) cycloalkyl; 9) amino groups; 10) sulfonyl; 11) nitro group; 12) halogen.

100121 Wherein the halogen is fluorine, chlorine, bronune and iodine.

[0013] R3 can denote I) hydrogen atom; 2) C1-Co at group; 3) C;;-C6 alkenyl; 4 7A-C6 [0014] A common preparation method in the present invention comprises the following steps: [0015] Step COG' CIOC Et3N R1-NH IR2

CIOC

[0016] Tetahydrofuran is added into a reactor as solution at a low temperature, and then amine is added as reactant, and then malonyl chloride is dropped slowly to be stirred for 1-5 hours in a low temperature; and the mixture is warmed to room temperature and reacted for 0.5-5 hours; compound IIis obtained by reduced-pressure distillation.

[0017] Ste COG' H 00C HOOCc-N.) [0018] Tetrahydrofuran is added into a reactor as solution at a low temperature, and then P3irrolidine-3-carboxylic acid is added as reactant; and a certain amount of trithylamine is added then, finally compound of formula 11 is slowly added, after 1-5 hours of stirring at low temperature, the reaction mixture is warmed to room temperature and reacted for 0.5-5 hours. A reaction process is monitored with gas chromatography(GC), and after the reaction finishes, compound of formula 111 is obtained by reduced-pressure distillation.

[0019] Step 3: HO--,"..OH i NaH + R3-01 L'-N--- .--

---N R i

R (VI)

[0020] Under inert gas, methyl benzene is added into the reactor, and 3,5-dihydroxypiperidines and sodium hydride are added in sequence, after stirring 1 hour in room temperature, halogenated hydrocarbons is slowly added into the reactor to be reacted for 1-5 hours in a heating condition. After the reaction finishes, catalyst quench is performed; compound of -formula la is obtained by column chromatography separation finally.

[002.11 Step 4:

HOOC

-N \ .R1

0 4, N, 0 R2 [0022] In low temperature, compound of formula III, methyl benzene, compound of formula IV, trithylamine are added into the reactor in sequence, after stirring for 0.5-1 hour, the temperature rises to 40-120°C slowly, and the reaction process is monitored with TLC; after the reaction finishes, target product is obtained by recrystalization.

[0023] The pharmaceutically acceptable salt covers the salts which is non-toxic to living organism and formed by the formula I and inorganic acid or organic acid, and acid can be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, methanoic acid, acetic acid, propanoic acid, citric acid, lactic acid, dihydroxysuccinic acid, oxalic acid, malic acid, citric acid, ascorbic acid, benzoic acid, salicylic acid, caffeic acid, malonic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and so on.

[0024] The preferred compound is compound of formula IA and salt: 0, R3

H N (IA)

[0025] Wherein R1, R2, R3 are groups as defined for the compound of formula I [0026] In preferred compounds, the further steps of step 1 is: Tetrahydrofuran is added into a reactor as solution at a low temperature, and then amine is added as reactant, and then maionyl chloride is dropped slowly to be stirred for 1-2 hours in a low temperature, and the mixture is warmed to room temperature and reacted for 0.5-2 hours; compound of formula IIA is obtained by reduced-pressure distillation [0027] In preferred compounds, the further steps of step 2 is: Tetrahydrofuran is added into a reactor as solution at a low temperature, and then Pyrrolidine-3-carboxylic acid is added as reactant, and compound of formula II is slowly added, after 1-2 hours of stirring at low temperature, the reaction mixture is warmed to room temperature and reacted for 0.5-2 hours. A reaction process is monitored with gas chromatography(GC), and after the reaction finishes, compound of formula III A is obtained by the column chromatography separation.

[0028] In preferred compounds, the further steps of step 3 is: Under inert gas, methyl benzene is added into the reactor, and 3,5-dihydroxypiperidines and catalyst are added in sequence, after stirring 1 hour in room temperature, halogenated hydrocarbons is slowly added into the reactor to be reacted for 1-2 hours in a heating condition. After the reaction finishes, catalyst quench is performed; compound of formula VA is obtained by column chromatography separation finally.

[0029] In preferred compounds, the further steps of step 4 is: In low temperature, compound of formula III, methyl benzene, compound of formula V. trithylamine are added into the reactor in sequence, after stirring for 0.5-1 hour, the temperature rises to 40-60C slowly, and the reaction process is monitored with TLC; after the reaction finishes, target product is obtained by recrystalization.

[0030] Wherein above conditions: low temperature is -25°C-5°C; room temperature is 15°C-30°C; TLC is thin layer chromatography; inert gases are argon and nitrogen; an application of the formula IA or the pharmaceutically acceptable salt on renin inhibitors.

ADVANTAGES OF THE INVENTION

[0031] The present invention is a new renin inhibitor with pyrrolidine-3-carboxylic acid-3-dimepiperate stmcture, which has a simple synthetic process and adapt to industrial production [0032] The present invention has a remarkable inhibitory function to renin, a long action duration and small toxic effect on the human body.

DETAILED DESCRIPTION OF THE INVENTION

[0033] Embodiment 1 Chemical formula 1:

NH

[0034] A synthesizing process as follows: Cod THF HOOC -N H2 CIOC_/ -20°C step

HOOC / 0 NH

HOOC

HO OH CI NaH 2/ \ / step 3 0 1k---NH 0 0 0 O-

N \(:)

NH

step 4 [0035] Step I: with the temperature of -20°C, 25m1 of Tetrahydrofuran(THF) is added into a three-necked round bottomed flask, and then 25.3m1 of 2M solution of Methylamine in Tetrahydrofuran is added in as reactant, and finally 7.1g of Malonyl dichloride is slowly dropped in, a mixture 1 is stirred for 1 hour at low temperature and then reacts for 0.5 hour when the temperature rise to the room temperature; Methylamine and Malonyl dichloride are obtained by a reduced pressure distillation.

[0036] Step 2: with the temperature of -20°C, 20m1 of Tetrahydrofuran(THIF) is refiled in the three0-necked round bottomed flask being distilled, and then 10mol% of Triethylamine is added into and finally 5.75g of Pyrrolidine-3-carboxylic acid is slowly added into, and then a mixture 2 is stirred for 1-2 hours at the low temperature, and then reacts for 1 hour when the temperature rises to the room temperature; a reaction process is monitored with GC, and 9.6g of intermediate compound III is obtained by distillation after the reaction finishes with a productive rate of 90%.

[0037] Step 3: with a protection of indifferent gas, 30m1 of NIethylbenzene is added into a reactor as solution, and then 5.3g of 3,5-Dihydroxypiperidine are added into later, and then 1.1g of Sodium hydride is slowly added in three lots with the low temperature, and after a mixture 3 is stirred for 1-2 hours in the room temperature, 2.5ml of Chloromethane and Diethyl ether solution is slowly added into the reactor to react for 1.5 hours; after the reaction finishes, Aqueous ammonium chloride is slowly dropped to quench,and finally 5.8g of intermediate compound VI is obtained by separation with a productive rate of 98% [0038] Step 4: with the temperature of -10°C, 35m1 of Methylbenzene, 5.8g of intermediate compound VI and 9.5g of intermediate compound III are added into three-necked round bottomed flask in sequence, and then 2mol% of Titanium n-propoxide is added in to be stirred for 1 hour and then the temperature slowly rises to 100°C, and then moisture is steamed out by heating, and then a reaction process is monitored with CG; after the reaction finishes, white solid is obtained by recrystallization of Hexane and Dichloromethane(5:1), and 12.7g of the white solid is obtained after a desiccation with a productive rate of 87.5%. m.p. 420-421°C, in NMR. (CDC13, 400M): 65.87 (s, 1H), 4.92 (s, 1H), 4.02 (s, 1H), 3.94 (s, 1H), 3.77 (s, tH), 3.57 (d, J= 12.3 Hz, 2H), 3.50 (s, 1H), 3.34 -3.30 (m, 3H), 3.11 (s, 1H), 3.06 (t, J = 7.5 Hz, 3H), 2.86 (s, 111), 2.82 -2.78 (m, 3H), 2.75 (s, 1H), 2.44 (s, tH), 2.35 (s, 1H), 2.19 (s, 1H), 1.57 (s, 11-1), 1.21 (s, IH). I3C (CDC13, 1007\4): 6 172.1, 168.8, 161.5, 75.0, 69.1, 56.4, 50.8, 49.9, 48.0, 46.8, 44.7, 37.5, 36.0, 28.9, 26.6. APC1-MS 328.38 [M+H] + [0039] Embodiment 2 Chemical formula 2: 0 0 [0040] A synthesizing process as follows: N H2 + coo THF HOOC. cloc -20°C

step 1

HOOC :',7

0 /.7-NH + CI NaH HOOC step 3 LN; e 0 NH 011) 0 0 0 _,.._ ---\ )\-I step 4 /)---0 __1 H HN ----/ (I) [0041] Step 1: with the temperature of -20°C, 25m1 of Tetrahydrofuran(THT) is added into a three-necked round bottomed flask, and then 4.7g of Aniline is added, and finally 7.1g of Malonyl dichloride is slowly dropped in, and a mixture 4 is stirred for 1 hour at low temperature and then reacts for 0.5 hour when the temperature rise to the room temperature; 9.4g of compound in chemical formula 11 is obtained by the recrystallization after the reaction finishes, [0042] Step 2: with the temperature of -20°C, 20m1 of Tetrahydrofuran(THF) is added in the three-necked round bottomed flask, and then 9.0g of compound II, 10mol% of Triethylamine are added into and finally 5.47g of Pyrrolidine-3-carboxylic acid is slowly added, and then a mixture 5 is stirred for 1-2 hours at the low temperature, and then reacts for 1 hour when the temperature rises to the room temperature; a reaction process is monitored with GC, and after the reaction finishes, 11.8g of intermediate compound III is obtained in column chromatography separation with a productive rate of 90%.

[0043] Step 3: with a protection of indifferent gas, 30m1 of NIethylbenzene is added into a reactor as solution, and then 5.3g of 3,5-Dihydroxypiperidine are added into later, and then 1.1g of Sodium hydride is slowly added in three lots with the low temperature, and after a mixture 3 is stirred for 1-2 hours in the room temperature, 2.5ml of Chloromethane and Diethyl ether solution is slowly added into the reactor to react for 1.5 hours; after the reaction finishes, Aqueous ammonium chloride is slowly dropped to quench,and finally 5.8g of intermediate compound VI is obtained by separation with a productive rate of 98% [0044] Step 4: with the temperature of -10°C, 35m1 of Methylbenzene, 5.6g of intermediate compound VI and 11.8g of intermediate compound III are added into three-necked round bottomed flask in sequence, and then 2mol% of Titanium n-propoxide is added in to be stirred for 1 hour and then the temperature slowly rises to 100°C, and then the moisture is steamed out by heating, and then the reaction process is monitored with CG; after the reaction finishes, 14.8g of the white solid is obtained by the column chromatography separation with a productive rate of 89%. m.p. 503-504°C, 111NMR (CDC13, 500M): ö 7.56 -7.43 (m, 33H), 7.39 -7.32 (m, 4911), 7.10 (s, 16H), 4.90 (s, 14H), 4.20 -4.16 (m, 32H), 3.96(d, J = 61.7 Hz, 2611), 3.89 (s, 5H), 3.71 (d, J = 58.4 Hz, 3011), 3.64 (d, J = 5.7 Hz, 411), 3.55 (d, J = 4.6 Hz, 3011), 3.35 -3.3 1 (m, 4811), 3.10 (d, J = 9.1 Hz, 31H), 2.86 (s, 13H), 2.75 (s, 12H), 2.44 (s, 1211), 2.35 (s, 1211), 2.19 (s, 1211), 1.84 (s, I 2H), 1.25 (s, I 6H). I 3C (CDC13, I 25M): ö 172.1, 165.4, 161.8, 137.8, 129.4, 129.2, 123.7, 121.6, 121.4, 74.8, 69.0, 56.4, 49.8, 49.0, 47.9, 45.2, 45.0, 42.6, 36.7, 28.6. APCI-MS m/z: 390.45 [1\4+H]+ [0045] Embodiment 3 Chemical formula 3:

HN

NH

[0046] A synthesizing process as follows: \--NH2 + /COD THF HN HOOC -20°C COCI step 2 step 1

HOOC

HO--Th"-OH NaH HOOC-----, ---CI) AV') N + \ ..,-0,,,,)-NH step 3 0 0 --NH step 4 (I) [0047] Step 1: with the temperature of -20°C, 25m1 of Tetrahydrofuran(THF) is added into a three-necked round bottomed flask, and then 3..0g of Propyl amine is added in as reactant, and finally 7.1g of Malonyl dichloride is slowly dropped in, a mixture 6 is stirred for 1 hour at low temperature and then reacts for 0.5 hour when the temperature rise to the room temperature; Malonyl dichloride and Propylamine are obtained by the distillation after the reaction finishes.

[0048] Step 2: with the temperature of -20°C, 20m1 of Tetrahydrofuran(THIF) is reified in the three-necked round bottomed flask being distilled, and then 10mol% of Triethylamine is added into and finally 5.8g of Pyrrolidine-3-carboxylic acid is slowly added into, and then a mixture 7 is stirred for 1-2 hours at the low temperature, and then reacts for 1 hour when the temperature rises to the room temperature; a reaction process is monitored with GC, and 10.0g of intermediate compound III is obtained by distillation after the reaction finishes with a productive rate of 88%.

[0049] Step 3: with a protection of indifferent gas, 30m1 of NIethylbenzene is added into a reactor as solution, and then 5.3g of 3,5-Dihydroxypiperidine are added into later, and then 1.1g of Sodium hydride is slowly added in three lots with the low temperature, and after a mixture 3 is stirred for 1-2 hours in the room temperature, 2.5m1 of Chloromethane and Diethyl ether solution is slowly added into the reactor to react for 1.5 hours; after the reaction finishes, Aqueous ammonium chloride is slowly dropped to quench,and finally 5.8g of intermediate compound VI is obtained by separation with a productive rate of 98% [0050] Step 4: with the temperature of -10°C, 35m1 of Methylbenzene, 5.8g of intermediate compound VI and 10.0g of intermediate compound III are added into three-necked round bottomed flask in sequence, and then 2mol% of Titanium n-propoxide is added in to be stirred for 1 hour and then the temperature slowly rises to 100°C, and then moisture is steamed out by heating, and then a reaction process is monitored with CG; after the reaction finishes, 12.8g of the white solid is obtained by the column chromatography separation with a productive rate of 85%. m.p. 432-433°C, 1H NMR (CDC13, 500M): 64.81 (s, 1H), 4.66 (s, 1H), 4.02 (s, tH), 3.77 (s, 1H), 3.55 (dd, J = 14.6, 9.2 Hz, 4H), 3.34 -3.30 (m, 3H), 3.27 (s, 1H), 3.09 (dd, J= 15.6, 4.4 Hz, 4H), 2.88(d, J = 19.3 Hz, 2H), 2.75 (s, 1H), 2.45 (s, 1H), 2.20 (d, J = 14.4 Hz, 2H), 1.38(s, 1H), 1.26-1.22(m, 3H), 1.17 (s, 1H). 13C (CDC13, 125M):6 172.1, 166.8, 161.6, 75.0, 69.1, 56.43, 55.8, 49.9, 48.0, 46.8, 44.7, 41.4, 37.2, 36.0, 28.9, [0051] Embodiment 4 Chemical formula 4: [0052] A synthesizing process as follows: r-c-) cloc-^coa THF 15 NW.

COCI (H) -20°C

step 1 HO, -CI NaH step 3

COON

step 2 /

NH

HOOC"1---) step 4 [0053] Step 1: with the temperature of -20°C, 25m1 of Tetrahydrofuran(THT) is added into a three-necked round bottomed flask, and then 5.4g of Benzylamine is added, and finally 7.05g of Malonyl dichloride is slowly dropped in, and a mixture 4 is stirred for 1 hour at low temperature and then reacts for 0.5 hour when the temperature rise to the room temperature; 10.1g of compound in the chemical formula II is obtained by the recrystallization after the reaction finishes.

[0054] Step 2: with the temperature of -20°C, 20m1 of Tetrahydrofuran(THF) is added in the three-necked round bottomed flask, and then 10.18 of compound II, 10mol% of Triethylamine are added into and finally 5.47g of Pyrrolidine-3-carboxylic acid is slowly added, and then a mixture 5 is stirred for 1-2 hours at the low temperature, and then reacts for I hour when the temperature rises to the room temperature; a reaction process is monitored with GC, and after the reaction finishes, 12.7g of intermediate compound III is obtained in the column chromatography separation with a productive rate of 92%.

[0055] Step 3' with a protection of indifferent gas, 30m1 of Methylbenzene is added into a reactor as solution, and then 53g of 3,5-Dihydroxypiperidine are added into later, and then 1.1g of Sodium hydride is slowly added in three lots with the low temperature, and after a mixture 3 is stirred for 1-2 hours in the room temperature, 2.5ml of Chloromethane and Diethyl ether solution is slowly added into the reactor to react for 1.5 hours; after the reaction finishes, Aqueous ammonium chloride is slowly dropped to quench,and finally 5.8g of intermediate compound VI is obtained by separation with a productive rate of 98% [0056] Step 4: with the temperature of -10°C, 35m1 of Methylbenzene, 5.7g of intermediate compound VI and 12.7g of intermediate compound III are added into three-necked round bottomed flask in sequence, and then 2mol% of Titanium n-propoxide is added in to be stirred for 1 hour and then the temperature slowly rises to 100°C, and then the moisture is steamed out by heating, and then the reaction process is monitored with CG; after the reaction finishes, 13.8g of the white solid is obtained by the column chromatography separation with a productive rate of 78%. m.p. 514-515°C, 111NMR (CDC13, 500M):6 7.34 -7.25 (m, 511), 7.20 (s, 1H), 5.72 (s, 1H), 4.93 (s, 111), 4.60 (s, 1H), 4.51 (s, 111), 4.02 (s, 211), 3.96 (s, 1H), 3.77 (s, tH), 3.34 -3.30 (m, 4H), 3.11 (s, 1H), 3.06 (t, J= 7.2 Hz, 4H), 2.86 (s, tH), 2.75 (s, 1H), 2.44 (s, Hi), 2.36 (s, 1H), 2.19 (s, 1H), 1.58 (s, 1H), 1.22 (s, 1H). 13C (CDC13, 1251'vl): 6 172.1, 167.0, 161.8, 139.9, 128.5, 128.3, 127.7, 127.3, 126.9, 74.8, 69.0, 56.4, 49.8, 49.0, 47.9, 45.2, 45.0, 44.0, 42.4, 36.7, 28.6. APC1-MS m/z: 404.48 [M+H]E [0057] Embodiment 5 Chemical formula 5:

NH o °

[0058] A synthesizing process as follows: \-N H2 -sr CIOCCOC} THF -20°C step 1

NH

HOOC-

step 2 "OH NaH step 3 ONTh9 i-NH (I) c),-(\ step 4 [0059] The preparation procedure was the same as that described in embodiment I. [0060] The white solid, 13.5g, with a productive rate of 85%, m.p. 496-467°C, 1H NMR (CDC13, 500M): 5 9.76 (s, 1 H), 4.99 (s, 1 H), 4.02 (s, 3H), 3.83 -3.57 (m, 4 H), 3.48 (s, 1H), 3.13 (d, J = 4.3 Hz, 114), 3,12(s, 211), 3.12-2,88(m, 4H), 2.45 (s, 111), 214 (dd, J = 54.1, 3.0 Hz, 2H), 2.07 -2.05 (m, 2H), 1.92 (s, 1H), 1.73 -1.69 (m, 3H), 1.61 (s, 2H), 1.43-1.34 (m, 3H), 1.30-1.26(m, 4H). 13C (CDC13, 125M). 172.1, 166.8, 161.6, 75.5, 72.4, 69.1, 50.4, 49.9, 48.0, 46.80, 44.7, 41.4, 37.2, 34.8, 31.4, 31.4, 28.9, 25.9, 24.6, 24.6, 14.3. APCI-MS m/z: 410.26 [M+H]+ [0061] Embodiment 6 Chemical formula 6: NH 18 [0062] A synthesizing process as follows: T THF -20°C step 1 HN COOH 0 c )-NH // \-0 /

-N ( (HI)

step 2 HO. NaH HOOd HN (III) step 3 HO WI) step 4 9,\ 0 21-Th v (I) [0063] The preparation procedure was the same as that described in embodiment 1 [0064] The white solid, 14.2g, with a productive rate of 88%, m.p.526-527°C, 1H NMR (CDC13, 500M):8 7.34 -7.13 (m, 5H), 4.97 (s, 1H), 4.88 (s, 1H), 4.66 -4.59 (m, 211), 4.02 (s, 1H), 3.74 (t, J = 17.2 Hz, 3H), 3.56 (d, J = 35.8 Hz, 2H), 3.31 (s, 1H), 3.15 -2.94 (m, 5H), 2.86 (d, S = 0.8 Hz, 2H), 2.44 (s, 1H), 2.23 (d, J = 38.2 Hz, 2H), 1.99 (s, 1H), 1.31 -1.13 (m, 4H). 13C (CDC13, 125M): 172.1, 166.8, 161.8, 138.0, 128.3, 128.2, 128.1, 127.8, 73.4, 71.0, 69.0, 49.6, 49.0, 47.9, 45.2, 45.0, 42.4, 37.2, 36.0, 28.6, 14.3. APCI-MS m/z: 418.23 [NI+H]+ [0065] Embodiment 7 Chemical formula 7:

NNO

[0066] A synthesizing process as follows: -N H2 COG' CIOC-11

THF

-20°C step 1 HN HOOCN,_ A + COCI (II) step 2

HO DC

NH

HOOC NaH

step 3 HOO 0 N-7 (VI) (III) step 4 0 Pm (I) [0067] The preparation procedure was the same as that described in embodiment 1 [0068] The white solid, 15.3g, with a productive rate of 93%, m.p. 432-433°C, tHNMR (CDC13, 500M) 65.80 (s, 1H), 4.91 (s, 1H), 4.02 (s, 1H), 3.83 (s, 114), 3.78 (d, J = 6.5 Hz, 2H), 3.56 (s, tH), 3.55 -3.43 (m, 3H), 3.39 (s, 1H), 3.06 (t, J = 7.4 Hz, 3H), 2.86 (s, 111), 2.82 -2.78 (m, 31-I), 2.75 (s, 1H), 2.60 (s, 1H), 2.45 (s, 1H), 2.20 (s, 1H), 1.96 (s, 1H), 1.29 (s, 1H), 1.23-1.19(m, 4H). 13C (CDC13, 125M) 6 172.1, 165.36, 161.78, 135.18, 134.6, 130.1, 128.8, 127.6, 127.3, 126.6, 124.7, 121.9, 117.4, 74.2, 69.0, 65.0, 49.6, 49.0, 47.9, 45.2, 45.0, 42.6, 36.0, 28.6, 15.5. APCI-MS m/z: 342.20[M+H1+ [0069] Embodiment 8 Chemical formula 8: [0070] A synthesizing process as follows: e THF HN1-/

CIOC COCI -20DC

C

step 1 COCI HOOC (II)

K-N NH2 HO 0

step 3 (VI)

HN-

step 2 HO" OH

N

step 4 HOOC p CA 4- -_,,, ----\

N (III)

[0071] The preparation procedure was the same as that described in embodiment I. [0072] The white solid, 12.58, with a productive rate of 70%, m.p.726-727°C, 1H NIMR (CDC13, 500N4): 8 7.89 -7.71 (m, 4H), 7.54 (d, J = 6.4 Hz, 2H), 7.37 (d, J = 16.1 Hz, 21-1), 4.93 (s, 1H), 4.19 -4.15 (m, 2H), 4.02 (s, 11-1), 3.76 (d, J = 7.6 Hz, 2H), 3.71 (s, 1H), 3.55 (d, J= 11.1 Hz, 2H), 3.50 -3.42 (m, 2H), 3.11 (d, J = 1.8 Hz, 2H), 2.86 (s, 1H), 2.75 (s, 1H), 2.44 (s, 1H), 2.38 (s, 1H), 2.18 (s, 1H), 1.86 (s, 1H), 1.26 (s, 1H), 1.22-1.18 (m, 3H)0 13C (CDC13, 125M) 172.1, 168.2, 161.8, 134.0, 129.3, 121.6, 120.7, 120.1, 111.4, 95.4, 74.2, 69 0, 65 0, 49 6, 49.0, 47.9, 45 2, 45 0, 42 7, 36.0, 26 6, 15.5. APCI-MS m/z: 454.54 [M+1-1]+ [0073] Embodiment 9 Chemical formula 9: [0074] A synthesizing process as follows: COCI THF 22 HOOC", -NH2 coo 1\1) HN, -step 2 -20°C step 1

HOOC-

NH (,\ NaH / step 3 HO -'X'a"-*-*'"--> + Hntar.

(VI) - ^ NH

T-O 0 a *

step 4 (I) [0075] The preparation procedure was the same as that described in embodiment 1 [0076] The white solid, 10.8g, with a productive rate of 68%, m.p.608-609°C, 111NIMR (CDC13, 500M):5 7.34 -7.26 (m, 2H), 7.26 -7.17 (m, 7H), 7.08 (s, 1H), 6.59 (s, 1H), 4.67 (s, 1H), 4.65 -4.61 (m, 211), 4.58 (s, 1H), 4.48 (s, 1H), 4.02 (s, 1H), 3.77 (d, S = 3.6 Hz, 2H), 3.70 (s, 1H), 3.55 (s, 1H), 3.12 (d, S = 13.5 Hz, 2H), 3.09 -3.05 (m, 2H), 3.00 (s, 1H), 2.86 (s, 1H), 2.75 (s, 2H), 2.43 (s, 211), 2.27 (s, 1H), 2.18 (s, 2H), 1.74 (s, 1H). 13C (CDC13, 125M):172.1, 167.0, 161.8, 139.9, 138.0, 128.4, 128.4, 128.3, 128.3, 128.2, 128.2, 127.8, 127.6, 127.6, 126.9, 73.4, 71.0, 69.0, 49.6, 49.0, 47.9, 45.2, 45.0, 44.0, 45.2, 45.0, 44.0, 42.4, 35.4, 23.6. APCI-MS m/z: 480.24 [N/I+H]+ [0077] Embodiment 10 Chemical formula 10: [0078] A synthesizing process as follows:

THF HN

C100.--tOCI -20'C 0 COG' step 1 (II) 0 9 (71N112

HOOD step

COOH

NaH I-1 0 )- HOOC,, // HO 0 ----\ ..\,/ \ (VI) + -\ id ---/ b:./ oil) H2N step 3 step 4 (I) [0079] The preparation procedure was the same as that described in embodiment 1 [0080] The white solid, 11.6g, with a productive rate of 76%, m.p.693-694°C, 1H NN4R (CDC13, 500M): 67,31 (t, J = 20.9 Hz, 3H), 7.27-7.19 (m, 4H), 7.16 (s, 1H), 6.90 (s, 1H), 6.78 (s, 1H), 6.62 (s, 1H), 4.97 (s, 111), 4.65 -4.61 (m, 2H), 4.19 -4.15 (m, 2H), 4.10 -4.06 (m, 2H), 4.02 (s, tH), 3.94 (s, 1H), 3.76 (d, J = 8.5 Hz, 2H), 3.59 (s, tH), 3.31 (s, 1H), 3.10 (d, J = 8.0 Hz, 2H), 3.00 (s, 1H), 2.86 (s, 1H), 2.45 (s, 1H), 2.30 (s, 1H), 2.19 (s, 1H), 2.02 (s, 1H), 1.26 (s, 1H). 13C (CDCI3, 125M): 172.1, 165.7, 161.8, 143.3, 138.0, 128.3, 128.3, 128.2, 128.1, 127.8, 124.2, 118.0, 116.7, 73.4, 69.0, 49.6, 49.0, 47.9, 45.2, 45.0, 42.6, 36.0, 28.6.

[0081] Embodiment 11 Chemical formula 11: [0082] A synthesizing process as follows:

THF

Ci0C--MOCi -20°C Cod step step 1 0 (II) step 2 PC)' 11)N

HOOC-(III)

HN COOH

HO. OH NaH HO"-- HOOC /9 + 0 i (III) step 3 (VI) (I) [0083] The preparation procedure was the same as that described in embodiment 1 [0084] The white solid, 13.8g, with a productive rate of 85%, m.p.348-349°C, 1H NIV1R (CDC13, 500M) 54.92 (s, 1H), 4.07 (s, 1H), 4.02 (s, 111), 3.77 (s, 111), 3.59 (t, J = 14.2 Hz, 3H), 334-3.30(m, 3H), 31 1 (s, 1H), 3.09-3.04 (m, 3H), 2.88 -2.83 (m, 7H), 2.75 (s, 1H), 2.45 (s, 1H), 2.35 (s, 1H), 2.20 (s, 1H), 1.59 (s, 1H), 1.21 (s, 111). 13C (CDC13, 125M):172.1,170.2,161.0, 75.0, 69.1, 56.4, 50.8, 49.9, 48.0, 46.8, 44.7, 38.5, 36.7, 36.7, 36.0, 28.9. APC1-MS 342.2 [M+H]+ [0085] Embodiment 12 Chemical formula 12: [0086] A synthesizing process as follows:

THF L

NH CIOC--' COD COOH -20°C step 1 COCI 0 / 00 Is-step 2 HO, OH NaH HOOC 0 Nj V, '1,N-Th e (III) step3 HO' (VI) w step4 / (I) [0087] The preparation procedure was the same as that described in embodiment 1.

[0088] The white solid, 12.6g, with a productive rate of 80%, m.p.370-371°C, 1FINMR (CDC13, 500IYI): 34.91 (s, 1H), 4.02 (s, 111), 3.82-3.69 (m, 4H), 3.57 (d, J = 10.9 Hz, 2H), 3.44(s, 1H), 3.34-3.30(m, 3H), 3.26-313 (m, 2H), 3.11 (s, 1H), 3.06(t, J = 8.9 Hz, 3H), 2.86 (s, 1H), 2.75 (s, 1H), 2.44 (s, 1H), 2.34 (s, 1H), 2.19 (s, 1H), 1.57 (s, 1H), 1.24-1.18 (m, 7H). 13C (CDCI3, 125M): 172.1, 162.0, 161.0, 75.0, 69.1, 56.4, 50.8, 49.9, 48.0, 46.8, 44.7, 41.1, 41.1, 38.5, 36.0, 28.9, 13.2, 13.2. APCI-MS m/z: 370.23[NI+H]+ [0089] Experiment example 1 [0090] Testing on receptor antagonistic activity of Angiotensin II [0091] The test is done according to methods disclosed in "An activity determination on receptor antagonist of Angiotensin II" ("Journal of Beijing Medical University", vol.30, No. 4, Aug. 1998, page 270) written by Xiaowei Wang and etc..

[0092] About 100pg of Hepatic membrane protein, a certain amount of 1251-Angiotensin II receptor(about 5,000, counting rate/min), 0.045ng-30ng of Angiotensin II receptor without marking are added into 0.35m1 of rat liver cell membrane receptor reaction mixture, and then lpg of the Angiotensin II receptor is added into a non-special pipe to react for 70min in a temperature of 25°C, and then water bath stop reacting, and then a multi-head collector collects binding 125I-Angiotensin II receptor on fiberglass filter paper(a presaturation is done with Img/L of Angiotensin T), and then each tube is washed with 5m1 of flushing fluid each time for 3-4 times all together; a radioactivity is measured with ycounter and IC50 values are calculated [0093] The experiment result shows that IC50 values of the compounds 1-12 in above embodiments is less than or equal to 2pmol.

[0094] Experiment example 1 [0095] An inhibiting effect of human renin [0096] Synthetic compound and Pepride compound Nma-KHPFH LVIHK(Dnp)-NFI2 are mixed together, and then a fluorescence intensity (an excitation wavelength:365nm; measured wavelength:435nm) before the reaction is measured, and then human recombinant renin is added later to be cultivated for 3.5 hours in a temperature of 37°C, and then the fluorescence intensity after the reaction is measured with a fluorophotometer; inhibitory activity expressions of the compounds IC50 are as follows: Form 1 Embodiments IC50(nm) Embodiment 1 0.3 Embodiment 2 0.8 Embodiment 3 1.3 Embodiment 4 0.6 Embodiment 5 0.9 Embodiment 6 1.8 Embodiment 7 2.0 Embodiment 8 2.2 Embodiment 9 0.2 Embodiment 10 0.5 Embodiment 11 1.2 Embodiment 12 1.5 Comparative embodiment 1.6 Remark: the compound in comparative embodiment is Aliskiren.

[0097] The experiment shows that the compounds containing Pyrrolidine-3-carboxylic acid3-dimepiperate has a distinct inhibiting effect on renin.

[0098] Experiment example 3 [0099] Reduced pressure experiment [00100] In the experiment of conscious spontaneously hypertensive rat(SHRs), the compound in this invention has a ability to lower blood pressure; the comparative compound and the compound in this invention with equivalent doses (on a molar basis) of SHR5(250-300g) are provided to each group in consecutive three days, and after the medicine fed, systolic blood pressure and heart rate in different time point will be monitored with a telemetry; Results are listed in following Form 2: Form 2. Affect of the compound in this invention on the SBP(mmHg) Compound Basic blood 30min 24h 48h 72 pressure Embodiment 1 150 128 123 123 130 Embodiment 2 150 127 124 124 129 Embodiment 3 150 128 123 123 132 Embodiment 4 150 123 123 123 131 Embodiment 5 150 126 124 124 128 Embodiment 6 150 125 123 123 129 Embodiment 7 150 128 125 125 130 Embodiment 8 150 124 123 123 128 Embodiment 9 150 126 123 123 131 Embodiment 10 150 127 122 123 129 Embodiment 11 150 128 123 123 133 Embodiment 12 150 129 124 124 131 Comparativc 150 135 128 135 147 compound 1 Comparative 150 132 126 135 148 compound 2 Remark: the comparative compound 1 is Aliskiren, the comparative compound 2 is Losartan potassium.

[00101] The experiment shows that all the compounds 1-12 in this invention express the above-stated similar feature of lowering blood pressure. Compared with the comparative group, in whole treatment period, the compounds 1-12 in this invention express continues and strong ability to lower the blood pressure to a normal level with a long efficiency, which will not result in fluctuating sharply of the blood pressure and avoid a happening of heavy low blood pressure.

Claims (3)

1. CLAIMSCompound I shown below or pharmaceutically acceptable salt: R2 Wherein R denotes: I) hydrogen atom; RI denotes 1) CI-Ca alkyl group; 2) phenyl or substituted phenyl; 4) hydrogen atom; wherein sub:it:latent group of the substituted phenyl in RI is: 1) methyl; 2) ethyl; 3) propyl, 9) amino groups; 11) nitro group; 12) halogen, wherein the halogen is is fluorine, chlorine, bromine and iodine; R2 denotes 1) CI-Ca alkyl group; 2) phenyl or substituted phenyl; 4) hydrogen atom; wherein substituent group of the substituted phenyl in R2 is: 1) methyl; 2) ethyl; 3) propyl; 9) amino groups; 11) nitro group; 12) halogen, wherein the halogen is is fluorine, chlorine, bromine and iodine; 122 denotes 1) hydrogen atom* 2) C1-C6 alkyl group; 3) C.3-C6 cycloalkyl; 4) benzyl.
2. 2 The compound defined in claim I, wherein RI is 1) CI-Ca alkyl group; 2) phenyl; 3) hydrogen atom.
3. 3. The compound defined in claim 1, wherein R2 1S C1-C4 alkyl group; 2) phenyl, 3) hydrogen atom The compound defined in claim 1, wherein 111 is 1) methyl; 2) ethyl-3) benzyl.The compound defined in claim 1, wherein selected from: z -0 0 0 0 0 0 N-Jc-L N 0 H HN 0 0 / HN 0 Embodiment 2N NH )./ 0Embodiment 1 7 y 0 0 HN----j-I o 0 - 0 i- HN 0 0CONJ-NHEmbodiment 4NHEmbodiment 3NHN N *-*HEmbodiment 5 0 NHN all 0HEmbodiment 6 0, / --- Em -KH \--0 0 ----- 7' 0 N N.,0,---N)--O H L.! 1 HN,HCN 0 1'1"-' 0 0 H bodiment 8 Embodiment 7 \ 0 Emb H7N % ) 0 H40.,-----1, 0),-NH --.-\ \--- 0 NCI-fl HN N" 0 odiment 9 H Embodiment 10 07 I \ 9 Oz HN 0 0 / o N N HN 0 0 (--N -N 0 0Embodiment 11 Embodiment 12