This present application is the U.S. national stage of application No. PCT/CN2015/095758, titled ‘TRIPEPITIDE COMPOUND, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF”, filed on Nov. 27, 2015, which claims priority under 35 U.S.C. § 119(a) and 35 U.S.C. § 365(b) from Chinese Application No. 201410705180.3, titled ‘TRIPEPITIDE COMPOUND, PREPARATION :METHOD THEREFOR, AND APPLICATION THEREOF”, filed on Nov. 27, 2014, with the State Intellectual Property Office of the People's Republic of China, both of which are incorporated herein by reference in entirety.

FIELD

The present invention relates to novel compounds of formula (I) and corresponding pharmaceutically acceptable salts. The present invention also relates to a method for preparing the compounds or corresponding salts or intermediates thereof. The present invention also relates to a pharmaceutical composition of the compounds. The compounds have angiotensin converting enzyme inhibiting bioactivity, and the compounds and a pharmaceutical composition thereof play a role in preventing and treating hypertension and other cardiocerebral vascular system diseases.

BACKGROUND

The theme of World Health Day 2013 is to control hypertension. According to the survey data published by the World Health Organization (WHO), hypertension and its associated complications have become one of the major diseases that threaten human life and health, with a morbidity and mortality that have exceeded tumor diseases and rank first. There are about 1 billion hypertensive patients worldwide, resulting in 7.1 million cases of cardiovascular death each year, and if not controlled, in 2025 the number of patients will increase to 1.56 billion. Chronic Noncommunicable Disease Prevention and Control Center of the Chinese Center For Disease Control And Prevention has published the latest research results—in 2010, the prevalence of hypertension in Chinese adults was as high as 33.5%, and the total number of people with the disease was estimated to have exceeded 330 million. Hypertension is the most important risk factor for the morbidity and mortality of heart disease, stroke, kidney disease and diabetes. About 2 million deaths per year are associated with hypertension, and hypertension has become an important public health problem. (China News Network, Oct. 10, 2010 16:26) Hypertension and its complications have brought great economic burden to the society and families. So far, great progress has been made in the study of treatment of hypertension and its complications, but the pain of hypertensive patients can still not be completely solved. At the same time, the widespread hazards of hypertension and its complications have led to rapid development of the antihypertensive drug market. Over the past 30 years, hypertension is mostly treated by medicaments, and six categories of antihypertensive drugs, including diuretics, β-receptor blockers, α-receptor blockers, calcium antagonists (CCB), angiotensin converting enzyme inhibitors (ACEI), and angiotensin receptor antagonist (ARB), as well as their different combinations have gradually developed.

For angiotensin converting enzyme inhibition (ACEI), since the advent of captopril in 1981, design of drug using proline as the parent nucleus and targeting angiotensin converting enzyme (ACE, a zinc ion-containing exopeptidase) has being a research hotspot in the field of antihypertensive, and ACEI drugs and lead compounds of dipeptides and tripeptides containing thiol, carboxylic acid, phosphoric acid and other key functional groups have been designed successfully. So far, at least 17 ACEI drugs have become clinical first-line drugs for hypertension treatment. Other antihypertensive drugs have different emphasis, especially ARB antihypertensive drugs have gradually become an important part of antihypertensive drugs due to their long-acting effects and low side effects. However, in clinical cases, hypertensive patients are often accompanied by diabetes, kidney disease and other cardiovascular and cerebrovascular diseases. Only one antihypertensive drug often cannot achieve a desirable effect, so the combination of two or more antihypertensive drugs has become a trend of clinical antihypertensive drugs. Therefore, it is a trend to develop a multi-effect antihypertensive drugs which are more effective and suitable for multiple indications.

SUMMARY

The present invention provides a tripeptide compound with a structure of formula (I)


wherein, in formula (I),

R is represented by formula (II)



wherein, in formula (II).

R1is selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, alkenyl, alkynyl, acyl, aroyl, aryl, aralkyl, heteroaryl or heteroaralkyl:

R2is selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, alkenyl, alkynyl, acyl, aroyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkylthio, aralkylthio, arylthio, F, Cl, Br, I, NO2or CN:

R1and R2are the same or different;n=0, 1, 2, 3, 4, or 5; and when n≥2, multiple R1s are the same or different;

m=0, 1, 2, 3, 4, or 5; and when m≥2, multiple R2s are the same or different;

W is selected from


wherein


is linked to the benzene ring on the left side thereof; wherein Z is selected from oxygen or nitrogen, and R6is selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and

X is selected from oxygen or hydrogen;

wherein, in formula (I),

R′ is a residue of an L- or D-amino acid or amino acid derivative, as shown in formula (III), or R′ is absent, and



when R′ is a residue of an L- or D-amino acid or amino acid derivative, the C-terminus of


is linked to the N-terminus of


and the N-terminus of


is linked to the C-terminus of


and

when R′ is absent,


is linked to


via an amide bond or a C—N bond; and

wherein R4and R5are each independently selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and R4and R5are the same or different;

wherein, in formula (I),

R″ is represented by the formula (IV):



wherein:

Y is selected from oxygen, nitrogen or sulfur, and

when Y is nitrogen, R″″ is R7and R8, and R″ is



when Y is oxygen, R″″ is R9, and R″ is —OR9;

when Y is sulfur, R″″ is R10, and R″ is —SR10:

wherein, R7, R8, R9and R10may be the same or different, and are each independently selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl or heteroaralkyl;

wherein, in formula (I),

R′″ is selected from hydrogen or alkyl;

A=carbon:

L is selected from hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;

D is carbon or absent, t=0, 1, 2, 3; and

when D is carbon and B is carbon, A is linked to B by a carbon-carbon double bond or carbon-carbon single bond, and K and B and D are in a ring system; or A is linked to B by a carbon-carbon double bond or carbon-carbon single bond, and K is linked to B and is not linked to D;

wherein K and B and D are in a ring system, K is a selected from an alkyl or a heteroalkyl with a carbon atom number of 2 to 8, or an alkenyl with a carbon atom number of 3 to 8, or K together with B and D is formed into an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl;

when K is linked to B and is not linked to D, K is selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, hydroxy, alkoxy, aryloxy aryl, aralkyl, heteroaryl or heteroaralkyl;

when D is carbon and B is sulfur, A is linked to B via a carbon-sulfur single bond, and K is absent; and

when D is absent, B is carbon, and K is hydrogen;

wherein the alkyl, cycloalkyl, heteroalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl and heteroaralkyl groups may each be unsubstituted or optionally substituted with one or more substituents selected from hydroxy, alkoxy, aryloxy, thio, thioalkyl, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy, alkoxycarbonyl, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano or nitro group.

Optionally, R group


is selected from the following structures:



Optionally, R′ group


is selected from the following structures:



wherein, “*” represents a chiral center, and the compound comprising “*” includes all chiral isomers of the structural formula.

Optionally, when Y is oxygen, R9is a group selected from:

methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the following structures:



Optionally, when Y is nitrogen, R″ is a group selected from



wherein, “*” represents a chiral center, and the compound comprising “*” includes all chiral isomers of the structural formula.

Optionally, when Y is sulfur, R″ is a group selected from



wherein, “*” represents a chiral center, and the compound comprising “*” includes all chiral isomers of the structural formula.

Optionally, formula (I) is selected from the following formula structures:



wherein, “*” represents a chiral center, and the compound comprising “*” includes all chiral isomers of the structural formula.

Optionally, the tripeptide compound mentioned above is selected from the compounds of the following structures:

No.formula221S-1221S-2221S-3221S-4221S-5221S-6221S-7221S-8221S-9221S-10221S-11221S-12221S-13221S-14221S-15221S-16221S-17221S-18221S-19221S-20221S-21221S-22221S-23221S-24221S-25221S-26221S-27221S-28221S-29221S-30221S-31221S-32221S-33221S-34221S-35221S-36221S-37221S-38221S-39221S-40221S-41221S-42221S-43221S-44221S-45221S-46221S-47221S-48221S-49221S-50221S-51221S-52221S-53221S-54221S-55221S-56221S-57221S-58221S-59221S-60221S-61221S-62221S-63221S-64221S-65221S-66221S-67221S-68221S-69221S-70221S-71221S-72221S-73221S-74221S-75221S-76221S-77221S-78221S-79221S-80221S-81221S-82221S-83221S-84221S-85221S-86221S-87221S-88221S-89221S-90221S-91221S-92221S-93221S-94221S-95221S-96221S-97221S-98221S-99221S-100221S-101221S-102221S-103221S-104221S-105221S-106221S-107221S-108221S-109221S-110221S-111221S-112221S-113221S-114221S-115221S-116221S-117221S-118221S-119221S-120221S-121221S-122221S-123221S-124221S-125221S-126221S-127221S-128221S-129221S-130221S-131221S-132221S-133221S-134221S-135221S-136221S-137221S-138221S-139221S-140221S-141221S-142221S-143221S-144221S-145221S-146221S-147221S-148221S-149221S-150221S-151221S-152221S-153221S-154221S-155221S-156221S-157221S-158221S-159221S-160221S-161221S-162221S-163221S-164221S-165221S-166221S-167221S-168221S-169221S-170221S-171221S-172221S-173221S-174221S-175221S-176221S-177221S-178221S-179221S-180221S-181221S-182221S-183221S-184221S-185221S-186221S-187221S-188221S-189221S-190221S-191221S-192221S-193221S-194221S-195221S-196221S-197221S-198221S-199221S-200221S-201221S-202221S-203221S-204221S-205221S-206221S-207221S-208221S-209221S-210221S-221wherein, “*” represents a chiral center, and the compound comprising “*” includes all chiral isomers of the structural formula.

The present invention also provides a hydrolyzate of the compound above wherein Y is oxygen.

The present invention also provides an enantiomer, tautomer, stereoisomer, rotamer, diastereomer or racemate of the compound above.

The present invention also provides a pharmaceutically acceptable salt and a pharmaceutically acceptable ester of the compound above, wherein the pharmaceutically acceptable salt includes pharmaceutically acceptable acid salt and pharmaceutically acceptable basic salt, wherein the pharmaceutically acceptable acid salt includes a salt formed with one of the following acids: sulfuric acid, hydrogen sulfate, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, carbonic acid, boric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, butyric acid, pyruvic acid, maleic acid, malic acid, tartaric acid, citric acid, ascorbic acid, benzoic acid, camphoric acid, fumaric acid, oxalic acid, succinic acid, camphorsulfonic acid, maleic acid, salicylic acid or α-lactic acid; the pharmaceutically acceptable basic salt includes a salt formed by one of the following bases: alkali metals including lithium, sodium and potassium; alkaline earth metals including magnesium, and calcium; lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, butyllithium, ammonium, triethylamine, diisopropylethylamine, ornithine, arginine, lysine or histidine; and the pharmaceutically acceptable ester includes an ester formed through a hydroxyl group or a phenolic hydroxyl group in the compound with an acid.

The present invention also provides a solvated mixture of the compound above, wherein the solvate is one selected from water, methanol, ethanol, isopropanol, butanol, ethyl acetate and DMSO, or a combination thereof.

The present invention also provides a method for preparing the compound mentioned above, where the method comprises:



wherein,

when Y is selected from nitrogen or sulfur, step (2) ends after the synthesis of compound (1′), or step (2′) ends after the synthesis of compound (1″),

A, B, D, L, K, n, m, R1, R2, R4, R5, R′″, R″″, t, W and Y are as defined in any one of claims1-7:

a: protection of the amino of α-amino acid; P represents a suitable protecting group and is selected from tert-butoxycarbonyl(Boc), allyloxycarbonyl(Alloc), benzyloxycarbonyl, trityl, benzyloxymethyl, fluorenylmethoxycarbonyl(Fmoc), phthaloyl, dithiosuccinyl, methoxyformyl, ethoxyformyl, benzenesulfonyl, p-toluenesulfonyl, 2-(trimethylsilyl) ethanesulfonyl, benzyl(Bn), trityl(Tr) or allyl;

b: conditions for synthesis of peptide bond;

c: deprotection corresponding to step a;

e: the same as b:

f: the same as c;

g: the same as b;

g′: reductive amination;

h: conditions for ester hydrolysis;

wherein, “*” represents a chiral center, and the compound comprising “*” includes all chiral isomers of the structural formula.

On the other aspect, the present invention provides use of the compound mentioned above in the manufacture of a medicament for the prophylaxis, treatment or delay of hypertension and its complications, wherein the complications include one or more of coronary heart disease, angina pectoris, acute heart failure, chronic congestive heart failure, myocardial infarction and sequelae, congestive heart disease, myocardial ischemia, myocarditis, myocardial fibrosis, myocardial hypertrophy, atherosclerosis, benign small arterial nephrosclerosis, malignant small arterial nephrosclerosis, vascular growth abnormality and remodeling, angiogenesis-related diseases (such as new vascular macular degeneration), hyperaldosteronism, arrhythmia, kidney disease, diabetes, stroke, thrombosis, renal failure (such as diabetic nephropathy), hyperlipidemia, obesity, hyperglycemia, retinal arteriosclerosis, and hypertensive fundus lesions.

On the other aspect, the present invention provides a pharmaceutical composition comprising: the compound mentioned above, a pharmaceutically acceptable salt of the compound according to any one of claims1to8, a pharmaceutically acceptable carrier, excipient and diluent of the compound mentioned above.

On the other aspect, the present invention provides use of the above pharmaceutical composition in the manufacture of a medicament for the prophylaxis, treatment or delay of hypertension and its complications, wherein the complications include one or more of coronary heart disease, angina pectoris, heart failure (acute or chronic congestive heart failure), myocardial infarction and sequelae, congestive heart disease, myocardial ischemia, myocarditis, myocardial fibrosis, myocardial hypertrophy, atherosclerosis, benign small arterial nephrosclerosis, malignant small arterial nephrosclerosis, vascular growth abnormality and remodeling angiogenesis-related diseases (such as new vascular macular degeneration), hperaldosteronism, arrhythmia, kidney disease, diabetes, stroke, thrombosis, renal failure (eg, diabetic nephropathy), hyperlipidemia, obesity, hyperglycemia, retinal arteriosclerosis, and hypertensive fundus lesions.

The compound involved in the present invention has an effect of inhibiting the biological activity of angiotensin converting enzyme, and itself and its pharmaceutical composition has prevention and treatment effect on hypertension and other cardiovascular and cerebrovascular diseases.

