The Research On Angiotensin ? Receptor Antagonists As New Anti-hypertension Drugs

Hypertension is one of the common cardiovascular diseases. According to the reports of the 21 st annual meeting of International Society of Hypertension in 2009,there were about 972 million people worldwide suffer from hypertension or high blood pressure at present, which accounted for 26.4% of the adult population. The number would be 1.56 billion by 2025. In our country, there are about 200 million hypertension patients, and the number is increasing at the rate of 10% every year.Hypertension is a major risk factor of cardiovascular diseases, which convey risk of significant morbidity and mortality.There are many kinds of anti-hypertension drugs being used in clinic. However,most of them exists terrible side effects. Angiotensin ? receptor antagonist is a new kind of anti-hypertension drug, which comes after angiotensin converting anzyme inhibitior. From the first oral non-peptide angiotensin ? receptor antagonist was discovered, a lot of anti-hypertension drugs have been developed by medical companies. In clinic, these medicine show many advantages, such as good lowering blood pressure activity, fewer side effects, good tolerance, protecting target organs and improving potential fatal factors of cardiovascular diseases. Over 20 years has passed since the first angiotensin ? receptor antagonist appeared on the market. The angiotensin ? receptor antagonist has taken the lion's share of the market in anti-hypertension field with an amazing speed, replacing the dominant position of calcium ion antagonist.Big medical corporations abroad have occupied the majority part of the domestic market. It's urgency for us to develop new angiotensin ? receptor antagonist to break the monopoly.Research on this topic is about the design, synthesis and biological evaluation of new angiotensin ? receptor antagonists. Conventional design methods were taken in this research to design new compounds, using losartan as the lead compound.Losartan was divided into three parts, “heterocyclic area”, “biphenyl area” and “acid groups in ortho-position”. Many functional groups were chosen to replace these three parts. Several types of structures were designed, such as 5-nitro benzimidazole derivatives, spiro heterocycle derivatives, bi-benzimidazole derivatives, 6-substituted benzimidazole derivatives and 5-oxo-1,2,4-oxadiazole derivatives.1) Alka Bali proposed a drug-receptor interaction model that 5-substituted benzimidazole nucleus coupled through a methylene linker to pendent biphenyl system bearing a carboxyl group, and nitro group at 5-position, which had been found to be favorable for A? antagonism. Poss developed a series of A? receptor antagonists that contain N-phenyl indole group, which could extent the reduction time.Based on this, a series of 5-nitro benzimidazole derivatives were designed. 1, 4- and 1,5- disubstituted indoles were introduced to show which one could display a higher affinity. In addition, the appropriate alkyl groups were optimized through altering the length of alkyl chain.The synthesis of 5-nitro benzimidazole derivatives was accomplished starting from the suitable commercially available 4-nitro-benzene-1, 2-diamine(67), which reacted with different acyl chlorides in THF using Et3 N as base to give amide 68a-d.They were cyclized to produce benzoimidazoles 69a-d with con. HCl in Et OH.4-Methylindole 70 a was N-protected by acylation with benzoyl chloride in the presence of Et3 N and 4-(dimethylamino)pyridine(DMAP) to give(4-methyl-1H-indol-1-yl)(phenyl) methanone 71 a, which was brominated with NBS in the presence of AIBN to produce(4-bromomethyl-1H-indol-1-yl)(phenyl)methanone 72 a. 73a-d was obtained after reaction of 72 a with 69a-d in the presence of K2CO3, and then hydrolyzed with 2M aqueous Na OH. 73a-d reacted with2-fluoro-benzonitrile using K2CO3 as base in DMF yielded 74a-d. The final products61-64 were acquired after hydrolysis of 74a-d. Total yield was about 3.5%. The preparation of 65 and 66 were similar to 61-64. Total yield was about 3.5%.The above synthetic route was optioned because of the low yield.Indole-4/5-formaldehyde was used as the starting material, which coupled with 2-fluorobenzonitrile to give benzonitrile compound(77a-b); which was then hydrogenated and brominated to generate the halide component(79a-b). After substitution with 5-nitro benzimidazole derivatives(69a-d), the obtained benzonitrilecompounds(74a-f) were hydrolyzed to produce carboxylic acid compounds(61-66).Total yield was about 9.5%.2) Bernhart postulated that the role of the aromatic ring in “heterocyclic area” in the binding to the receptor was not necessary. This hypothesis was verified and found a new class of non-peptide AT1 antagonists. Base on this, a series of spiro heterocycle derivatives were designed.The synthesis of spiro heterocycle derivatives was accomplished starting from the suitable commercially available 1-? amino-cyclopentanecarboxam? ide, which reacted with different acyl chlorides in DCM using Et3 N as base to give amide 86a-d.They were cyclized to produce spiroazacyclic compounds 87a-d with 10 M KOH in Me OH. After substitution with the bromide(79a-b), the obtained benzonitrile compounds(88a-d, 89a-d) were cyclized to form tetrazole using with sodium azide to produce designed compounds(83a-d, 84a-d). Total yield was about 32% and 28%,respectively.3) Ries found that a series of benzimidazole derivatives that contained a hydrogen-bonding acceptor at 6-position could improve the affinity with receptor.Based on this, a series of bi-benzimidazole derivatives were designed.The substituted benzimidazoles(94a-e) were prepared from the commercially available methyl 4-amino-3-methylbenzoate(93) by four steps. The phenylamine(93)was reacted with alkyl acyl chloride in DCM, nitrated with concentrated nitric acid,hydrogenated with hydrogen and finally cyclized in acetic acid to produce benzimidazoles(94a-e). The obtained benzimidazoles were converted to the corresponding bis-benzimidazole derivatives(95a-e) by reacting with 2 M Na OH, and cyclized with N-methylbenzene- 1, 2-diamine in the presence of polyphosphorous acid. Each bis-benzimidazole derivatives(95a-e) was reacted with an indole bromide(79a or 79b) to generate benzonitrile derivatives(96a-e, 97a-e). The obtained benzonitrile compounds(96a-e, 97a-e) were hydrolyzed to produce carboxylic acid compounds(90a-e, 91a-e). Total yield was about 5.7% and 4.1%, respectively.The aforementioned synthetic route was not amenable to scale-up, where the preparation of heterocyclic amine could be in high yield, but the bromide fragment suffered from low yields coupled with complex manipulative procedures. The synthesized benzonitrile compound(96c) showed low solubility in 50% methanol in water with a low hydrolysis rate. To improve the reaction, we adjusted the order of the reactions. The benzyl alcohol compound(78a) was first hydrolyzed to give benzoic acid compound(99a), which was then esterified to form ethyl benzoate compound(100a). After brominating the ester, the bromide fragment was reacted with the heterocyclic amines in DMF. Without separation after reaction, 1-2 m L 2 M Na OH aqueous solution was added to the reaction mixture and stirred for another 1-2 h at room temperature which eliminated the ester to give the final products 90 c. Total yield was about 9.0%. About 200 g of 90 c was produced totally.4) Different functional groups were introduced into benzimidazole at 6-position to increase hydrogen-bonding acceptors, which might help to find several improve the affinity with receptor. Based on this, a series of 6-substituted benzimidazole derivatives were designed.The synthesis of 6-substituted benzimidazole derivatives was based on their different substituted groups. Benzoxazoles or oxazolo[4,5-b]pyridines(116a-i) were acquired after benzimidazole-6- carboxylic acid(114a-c) condensed with different ortho-aminophenols(115a-c). The amide derivatives(120a-f) were obtained after benzimidazole-6- carboxylic acid(114a-c) condensed with different amines(119a-b).6-pyridine benzimidazole derivatives(129a-c) was synthesized from the commercially available 2-bromopyridine(121), which was reacted with3-methylphenylmagnesium bromide to give the coupling product, 123; which was then nitrated with concentrated nitric acid and then hydrogenated to produce amino compound. Acylation of the resulting amino compound with alkyl acyl chloride in DCM, nitration, hydrogenation, and formation of the benzimidazole were performed to give the 6-pyridine benzimidazole derivatives(129a-c). Each prepared compounds(116a-i, 120a-f, 129a-c) was reacted with an indole bromide(79a-b, 118a-b) to generate the final compounds. Total yield was about 6.1%, 9.5% and 2.2%respectively.5) It was reported that receptor bound to the oxadiazole ring by hydrogen bonding, and the bond distance was shorter than that between receptor and the tetrazole ring. This action could improve the affinity with receptor. Based on this, a series of 5-oxo-1,2,4-oxadiazole derivatives were designed.5-oxo-1,2,4-oxadiazole derivatives were prepared starting from corresponding commercially available indole formaldehyde compounds(75a-b) by reacting with 2-fluorobenzonitrile. They were then hydrogenated to generate alcohol compounds(78a-b). The obtained alcohols were chlorinated to give chloride compounds(82a-b).They were then coupled with imidazole compound 132 to form disubstituted indole compounds(133a-b). After oxidizing the resulting compounds, the gained carboxylic acid compounds(134a-b) were reacted with methyl iodide to produce methylbenzoate compounds(135a-b). After the addition reactions of the esters and hydroxylamine hydrochloride, the N-hydroxy carboxamidine compounds(136a-b)were obtained. The carboxamidines were cyclized through the condensation reaction using CDI to yield 5-oxo-1,2,4-oxadiazole compounds(137a-b). The designed compounds 138a-b were obtained through the hydrolyzation of compounds 137a-b.Total yield was about 16.9%.6) At each stage of the synthetic sequence the product was isolated, purified by column chromatography and characterized by NMR and mass spec techniques.7) The results of radio-ligand binding assay showed that all the designed compounds displayed good affinity to the receptor. Most of them had better receptor affinity than losartan, while some of them were better than telmisartan, like 90b-d,91c-e, 92 and 108 a.The biological evaluation on spontaneously hypertensive rats showed that most of the designed compounds displayed anti-hypertension activity and varied from each other. Compounds 63, 83 b, 84 b, 90 c and 137 a had great anti-hypertension activities and deserved for further research.In conclusion, 5 series of new angiotensin ? receptor antagonists were designed,synthesized and pharmacologically evaluated. Among them, compounds 63, 83 b, 84 b,90c and 137 a had great anti-hypertension activities and deserved for further research.