阅读说明：本技术 一种新型肾素抑制剂 (Novel renin inhibitor ) 是由 张聿 于 2020-04-02 设计创作，主要内容包括：一种含吡咯烷-3-甲酸-3-哌啶酯结构的新型肾素抑制剂,可用于治疗与阻断RAS系统相关的疾病,包括高血压、心脏病等。具体涉及一种式(I)所示的化合物或其药学上可接受的盐。<Image he="392" wi="700" file="DDA0002436149810000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>式中R表示低级烷烃或环烷烃、芳基或取代芳基,R<Sub>1</Sub>、R<Sub>2</Sub>分别表示C<Sub>1</Sub>-C<Sub>4</Sub>的烷基、芳基或取代芳基、稠芳基或取代的稠芳基,R<Sub>3</Sub>表示低级烷基或环烷基、取代苄基。(A novel renin inhibitor containing pyrrolidine-3-carboxylic acid-3-piperidine ester structure can be used for treating diseases related to blocking RAS system, including hypertension, heart disease, etc. In particular to a compound shown as a formula (I) or pharmaceutically acceptable salt thereof. Wherein R represents a lower alkane or cycloalkane, aryl or substituted aryl group, R 1 、R 2 Respectively represent C 1 ‑C 4 Alkyl, aryl or substituted aryl, fused aryl or substituted fused aryl of (A), R 3 Represents lower alkyl or cycloalkyl, substituted benzyl.)

1. A compound (I) shown below or a pharmaceutically acceptable salt thereof:

wherein

R can be represented as: 1) a hydrogen atom; 2) c₁-C₆Alkyl groups of (a); 3) c₁-C₆Alkenyl of (a); 4) c₃-C₆Cycloalkyl groups of (a); 5) phenyl or substituted phenyl; 6) benzyl or substituted benzyl; 7) pyridyl or substituted pyridyl; 8) quinolinyl or substituted quinolinyl; 9) indolyl or substituted indolyl.

R₁Can be represented by 1) C₁-C₄2) phenyl or substituted phenyl, 3) pyridyl or substituted pyridyl, 4) pyrazolyl or substituted pyrazolyl, 5) indolyl or substituted indolyl, 6) benzofuranylOr substituted benzofuranyl, 7) quinolinyl or substituted quinolinyl, 8) chromanyl or substituted chromanyl, 9) dihydrobenzofuranyl or substituted dihydrobenzofuranyl, 10) indazolyl or substituted indazolyl, 11) pyrrolopyridyl or substituted pyrrolopyridyl, 12) benzisoxazolyl or substituted benzisoxazolyl, 13) indolinyl or substituted indolinyl, 14) quinazolinyl or substituted quinazolinyl, 15) dihydroquinazolinyl or substituted dihydroquinazolinyl, 16) furopyridyl or substituted furopyridyl, 17) isoquinolyl or substituted isoquinolyl, 18) pyrrolopyrimidyl or substituted pyrrolopyrimidyl, 19) tetrahydroquinolinyl or substituted tetrahydroquinolinyl, 20) tetrahydroindazolyl or substituted tetrahydroindazolyl, 21) tetrahydrocyclopentapyrazolyl or substituted tetrahydrocyclopentapyrazolyl, 22) Pyrrolyl which may be substituted, 23) imidazolyl or substituted imidazolyl, 24) pyrazolyl or substituted pyrazolyl, 25) pyrrolyl or substituted thienyl, 26) thiazolyl or substituted thiazolyl, 27) triazolyl, 28) pyrimidinyl, 29) pyrazinyl or substituted pyrazinyl, 30) imidazopyridinyl or substituted imidazopyridinyl, 31) pyrrolopyrazinyl, 32) hydrogen atom.

R₂Can be represented by 1) C₁-C₄Alkyl of (2), phenyl or substituted phenyl, 3) pyridyl or substituted pyridyl, 4) pyrazolyl or substituted pyrazolyl, 5) indolyl or substituted indolyl, 6) benzofuranyl or substituted benzofuranyl, 7) quinolinyl or substituted quinolinyl, 8) chromanyl or substituted chromanyl, 9) dihydrobenzofuranyl or substituted dihydrobenzofuranyl, 10) indazolyl or substituted indazolyl, 11) pyrrolopyridyl or substituted pyrrolopyridyl, 12) benzisoxazolyl or substituted benzisoxazolyl, 13) indolinyl or substituted indolinyl, 14) quinazolinyl or substituted quinazolinyl, 15) dihydroquinazolinyl or substituted dihydroquinazolinyl, 16) furopyridyl or substituted furopyridyl, 17) isoquinolinyl or substituted isoquinolinyl, 18) Pyrrolopyrimidyl or substituted pyrrolopyrimidyl, 19) tetrahydroquinolinyl or substituted tetrahydroquinolinyl, 20) tetrahydroindazoleA radical or substituted tetrahydroindazolyl, 21) a tetrahydrocyclopentapyrazolyl or substituted tetrahydrocyclopentapyrazolyl, 22) a pyrrolyl which may be substituted, 23) an imidazolyl or substituted imidazolyl, 24) a pyrazolyl or substituted pyrazolyl, 25) a pyrrolyl or substituted thienyl, 26) a thiazolyl or substituted thiazolyl, 27) a triazolyl, 28) a pyrimidinyl, 29) a pyrazinyl or substituted pyrazinyl, 30) an imidazopyridinyl or substituted imidazopyridinyl, 31) a pyrrolopyrazinyl, 32) a hydrogen atom.

R₃Can be expressed as: 1) a hydrogen atom; 2) c₁-C₆Alkyl groups of (a); 4) c₃-C₆Cycloalkyl groups of (a); 5) a substituted benzyl group.

2.A compound according to claim 1, wherein R represents a hydrogen atom.

3. The compound according to claim 1 and claim 2, wherein R₂Is C₁-C₄Alkyl group of (2), hydrogen atom.

4. A compound according to any one of claims 1-3, wherein R₂Is represented by C₁-C₄Linear alkyl group of (1).

5. The compound according to any one of claims 1-4, wherein R₃Is methyl, cycloalkyl, benzyl.

6. The compound according to claims 1-5 is selected from:

7. the compound of claims 1-6, or a pharmaceutically acceptable salt thereof.

8. The compounds according to any of claims 1 to 7 for the prophylaxis and treatment of diseases which are associated with hypertension, congestive heart failure, renal insufficiency, cardiac insufficiency, glomerulonephritis, renal colic, complications resulting from diabetes, glaucoma, elevated intraocular pressure, atherosclerosis, complications following vascular or cardiac surgery, hyperaldosteronism and diseases which are associated with the renin-angiotensin system.

Technical Field

The present invention relates to a novel renin inhibitor. The invention particularly relates to pyrrolidine-3-formic acid-3-piperidine ester compounds, a preparation method and an effect of the compounds as renin inhibitors.

Background

Chronic sustained activation of the renin-angiotensin-aldosterone system (RAAS) is an important factor in the development and progression of cardiovascular disease, renal disease, and diabetes. Thus, RAAS has become a major pathophysiological target for intervention in the above-mentioned diseases. Blocking the pathophysiological effects of RAAS can occur from three sites: angiotensin Converting Enzyme Inhibitors (ACEIs) reduce the conversion of angioangiotensinogen to angiotensin i (angi); angiotensin ii receptor Antagonists (ARBs) block the action of angiotensin ii (Ang 11); the renin inhibitor can block RAAS from the source to effectively reduce the generation of AngI and AngII. Previous studies have shown that ACEI or ARB blockade of RAAS leads to a compensatory increase in plasma renin activity and accumulation of AngI, which in turn activates RAAS leading to the "escape of angiotensin II". Inhibition of renin, in turn, can block and reduce overall RAAS activity and can be a rational treatment for potential benefit.

Renin is a renin protease synthesized mainly by paracoccular cells of the kidney, has species specificity, is first synthesized into inactive prorenin (prorenin), is then processed intracellularly to remove several amino acids to become single-chain active renin, is stored in secretory granules, is released into blood or tissues when being stimulated by external environment, promotes prorenin to be changed into renin, is influenced by the factors of hypotension, hyponatremia or in vivo volume reduction to stimulate renin release by paracoccular cells, increases renin release by sympathetic nerve stimulation (mediated by kidney β receptor), inhibits renin release by AT receptor negative feedback, previously, it is considered that renin has only a function of catalyzing angiotensinogen hydrolysis to produce AngI.however, with the discovery of renin receptor, it is recognized that renin, besides the role of enzymatic activity in free form, promotes angiotensin production, triggers a new signal different from angiotensin receptor signal, when renin receptor binding with renin receptor, catalyzes the role of renin hydrolysis to produce Angel receptor activity, plays a role of renin receptor activity in free form, and plays a role of potentiating the role of renin receptor of renin, which promotes angiotensin receptor activity of renin, which promotes angiogenesis of angiotensin receptor, promotes angiotensin receptor activity of angiotensin receptor, promotes angiogenesis, promotes the formation of angiogenesis, and promotes the formation of angiogenesis of angiotensin receptor, and promotes the formation of angiogenesis, and promotes the formation of angiogenesis of angiocardiopathy of angiogenesis, and myocardial ischemia, and promotes the cardiovascular receptor, and promotes the formation of myocardial ischemia, and myocardial ischemia, etc. the development of angiogenesis, and myocardial ischemia, and myocardial ischemia-myocardial ischemia, myocardial ischemia-myocardial.

Although the use of 3, 4-substituted piperidine compounds in the manufacture of renin inhibitors is disclosed in International publication No. 06/069788. However, no details of pyrrolidine-3-carboxylic acid-3-piperidine esters are mentioned in this publication.

Disclosure of Invention

The present invention provides a novel compound having an excellent renin inhibitory action.

The invention relates to a novel renin inhibitor, in particular to a substituted pyrrolidine-3-formic acid-3-piperidine ester derivative with a general formula (I) or a pharmaceutically acceptable salt thereof.

In the formula:

r can be represented as: 1) a hydrogen atom; 2) c₁-C₆Alkyl groups of (a); 3) c₁-C₆Alkenyl of (a); 4) c₃-C₆Cycloalkyl groups of (a); 5) phenyl or substituted phenyl; 6) benzyl or substituted benzyl; 7) pyridyl or substituted pyridyl; 8) quinolinyl or substituted quinolinyl; 9) indolyl or substituted indolyl.

R₁Can be represented by 1) C₁-C₄Linear alkyl of (a), 2) phenyl or substituted phenyl, 3) pyridyl or substituted pyridyl, 4) pyrazolyl or substituted pyrazolyl, 5) indolyl or substituted indolyl, 6) benzofuranyl or substituted benzofuranyl, 7) quinolinyl or substituted quinolinyl, 8) chromanyl or substituted chromanyl, 9) dihydrobenzofuranyl or substituted dihydrobenzofuranyl, 10) indazolyl or substituted indazolyl, 11) pyrrolopyridyl or substituted pyrrolopyridyl, 12) benzisoxazolyl or substituted benzisoxazolyl, 13) indolinyl or substituted indolinyl, 14) quinazolinyl or substituted quinazolinyl, 15) dihydroquinazolinyl or substituted dihydroquinazolinyl, 16) furopyridyl or substituted furopyridyl, 17) isoquinolinyl or substituted isoquinolinyl, 18) Pyrrolopyrimidinyl or substituted pyrrolopyrimidinyl, 19) tetrahydroquinolinyl or substituted tetrahydroquinolinyl, 20) tetrahydroindazolyl or substituted tetrahydroindazolyl, 21) tetrahydrocyclopentapyrazolyl or substituted tetrahydrocyclopentapyrazolyl, 22) pyrrolyl which may be substituted, 23) imidazolyl or substituted imidazolyl, 24) pyrazolyl or substituted pyrazolyl, 25) pyrrolyl or substituted thienyl, 26) thiazolyl or substituted thiazolyl, 27) triazolyl, 28) pyrimidinyl, 29) pyrazinyl or substituted pyrazinyl, 30) imidazopyridinyl or substituted imidazopyridinyl, 31) pyrrolopyrazinyl, 32) a hydrogen atom.

The substituted radicals can be selected from one or two of the following groups 1) to 12), which are identical or different, i.e.:

1) a methyl group; 2) an ethyl group; 3) propyl; 4) an alkoxy group; 5) an acyl group; 6) a cyano group; 7) an ester group; 8) a cycloalkyl group; 9) an amino group; 10) a sulfonyl group; 11) a nitro group; 12) halogen element

Wherein halogen is fluorine, chlorine, bromine and iodine.

R₂Can be represented by 1) C₁-C₄Linear alkyl of (a), 2) phenyl or substituted phenyl, 3) pyridyl or substituted pyridyl, 4) pyrazolyl or substituted pyrazolyl, 5) indolyl or substituted indolyl, 6) benzofuranyl or substituted benzofuranyl, 7) quinolinyl or substituted quinolinyl, 8) chromanyl or substituted chromanyl, 9) dihydrobenzofuranyl or substituted dihydrobenzofuranyl, 10) indazolyl or substituted indazolyl, 11) pyrrolopyridyl or substituted pyrrolopyridyl, 12) benzisoxazolyl or substituted benzisoxazolyl, 13) indolinyl or substituted indolinyl, 14) quinazolinyl or substituted quinazolinyl, 15) dihydroquinazolinyl or substituted dihydroquinazolinyl, 16) furopyridyl or substituted furopyridyl, 17) isoquinolinyl or substituted isoquinolinyl, 18) Pyrrolopyrimidinyl or substituted pyrrolopyrimidinyl, 19) tetrahydroquinolinyl or substituted tetrahydroquinolinyl, 20) tetrahydroindazolyl or substituted tetrahydroindazolyl, 21) tetrahydrocyclopentapyrazolyl or substituted tetrahydrocyclopentapyrazolyl, 22) pyrrolyl which may be substituted, 23) imidazolyl or substituted imidazolyl, 24) pyrazolyl or substituted pyrazolyl, 25) pyrrolyl or substituted thienyl, 26) thiazolyl or substituted thiazolyl, 27) triazolyl, 28) pyrimidinyl, 29) pyrazinyl or substituted pyrazinyl, 30) imidazopyridinyl or substituted imidazopyridinyl, 31) pyrrolopyrazinyl, 32) a hydrogen atom.

The substituted radicals can be selected from one or two of the following groups 1) to 12), which are identical or different, i.e.:

1) a methyl group; 2) an ethyl group; 3) propyl; 4) an alkoxy group; 5) an acyl group; 6) a cyano group; 7) an ester group; 8) a cycloalkyl group; 9) an amino group; 10) a sulfonyl group; 11) a nitro group; 12) halogen element

Wherein halogen is fluorine, chlorine, bromine and iodine.

R₃Can be expressed as: 1) a hydrogen atom; 2) c₁-C₆Alkyl groups of (a); 4) c₃-C₆Cycloalkyl groups of (a); 5) a substituted benzyl group.

The general preparation method of the invention comprises the following steps:

the method comprises the following steps:

adding Tetrahydrofuran (THF) into a reactor as a solvent at a low temperature, then adding reactant amine, finally slowly dropping malonyl chloride, stirring at the low temperature for 1-5 hours, and reacting for 0.5-5 hours after heating to the room temperature. The compound II is obtained by reduced pressure distillation.

Step two:

under the condition of low temperature, THF is added into a reactor as a solvent, a reactant pyrrolidine-3-formic acid is added, then a certain amount of triethylamine is added, finally the compound shown in the structural formula II is slowly added, the mixture is stirred for 1-5 hours at low temperature, and the reaction is continued for 0.5-5 hours after the temperature is raised to room temperature. The reaction was monitored by Gas Chromatography (GC) and when the reaction was complete, the compound of formula III was obtained by distillation under reduced pressure.

Step three:

under the protection of inert gas, adding toluene as a solvent into a reactor, then sequentially adding 3, 5-dihydroxypiperidine and sodium hydride, stirring for 1 hour at room temperature, slowly adding halogenated hydrocarbon into the reactor, and reacting for 1-5 hours under the heating condition. After the reaction is completed, the catalyst is quenched. And finally, separating by using column chromatography to obtain the compound with the structural formula VI.

Step four:

at a low temperature, sequentially adding a compound with a structural formula III, toluene, a compound with a structural formula IV and triethylamine into a reactor, stirring for 0.5-1 hour, slowly heating to 40-120 ℃, monitoring the reaction process by using T L C, and after the reaction is finished, obtaining a target product by using a recrystallization method.

Pharmaceutically acceptable salts include those salts of formula (I) which are non-toxic to living organisms formed with inorganic or organic acids, for example hydrochloric, sulphuric, nitric, phosphoric, formic, acetic, propionic, citric, lactic, tartaric, oxalic, malic, citric, ascorbic, benzoic, salicylic, caffeic, malonic, succinic, methanesulphonic, p-toluenesulphonic and the like.

Preferred compounds are compounds of the general formula (IA) and salts thereof:

wherein R is₁、R₂、R₃Are groups as defined above for compounds of formula (I).

In preferred compounds, the first step is further:

adding THF (tetrahydrofuran) as a solvent into a reactor at a low temperature, then adding reactant amine, finally slowly dropping malonyl chloride, stirring at the low temperature for 1-2 hours, and reacting for 0.5-2 hours after heating to the room temperature. Vacuum distillation is utilized to obtain the compound of the structural formula (IIA).

In a preferred compound, said second step is further:

adding THF (tetrahydrofuran) serving as a solvent into a reactor at a low temperature, adding a reactant pyrrolidine-3-formic acid, slowly adding a compound shown in a structural formula II, stirring at the low temperature for 1-2 hours, and heating to room temperature to continue reacting for 0.5-2 hours. The reaction was monitored by Gas Chromatography (GC) and when the reaction was complete the compound of formula (IIIA) was isolated by column chromatography.

In a preferred compound, said step three is further:

under the protection of inert gas, adding toluene as a solvent into a reactor, then sequentially adding 3, 5-dihydroxypiperidine and a catalyst, stirring for 1 hour at room temperature, slowly adding halogenated hydrocarbon into the reactor, and reacting for 1-2 hours under a heating condition. After the reaction is complete, the catalyst is quenched. And finally, separating by using column chromatography to obtain the compound with the structural formula (VA).

In preferred compounds, said step four is further:

at a low temperature, sequentially adding a compound with a structural formula V, toluene, a compound with a structural formula IV and triethylamine into a reactor, stirring for 0.5-1 hour, slowly heating to 40-60 ℃, monitoring the reaction process by using T L C, and after the reaction is finished, obtaining a target product by using a recrystallization method.

Among the above conditions:

the low temperature is-25 ℃ to 5 DEG C

Room temperature is 15-30 DEG C

T L C is thin layer chromatography

The inert gas is argon or nitrogen

Use of structural formula IA or a pharmaceutically acceptable salt thereof for the treatment of renin.

The invention has the beneficial effects

The invention relates to a novel renin inhibitor containing a pyrrolidine-3-formic acid-3-piperidine ester structure, which has simple synthetic process and is suitable for industrial production.

Has obvious inhibition effect on the renin, long action effect duration and small toxic action on human bodies.

Examples