- Preparation and purification method of olmesartan medoxomil key intermediate
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The invention relates to a preparation and purification method of a key intermediate 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{[2' -(triphenylmethyl-1H-tetrazole-5-yl) (1, 1'-biphenyl)-4-yl] methyl}-1H-imidazole-5-ethyl formate (I) for preparing a chemical drug olmesartan medoxomil for treating hypertension. The invention provides a preparation and purification method for generating a compound (I) by reacting 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) with N-(triphenylmethyl)-5-(4'-bromomethylbiphenyl-2-yl) tetrazole (III) in the presence of an organic solvent and an acid-binding agent. According to the preparation and purification method of the compound (I), the impurity content is effectively reduced, and the quality of a subsequent target productis improved. The method is stable in process, high in yield, good in quality, simple to operate, less in three wastes, low in production cost and suitable for industrial production, and the recoveredsolvent can be continuously used.
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Paragraph 0013-0024
(2020/07/02)
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- Preparation method of high purity olmesartan medoxomi I
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The invention relates to a preparation method of high purity olmesartan medoxomi I. The preparation method comprises following steps: 1,5-(4'-bromomethyl-1,1'-biphenyl-2-yl)-1-triphenylmethyl-1H-tetrazole (A) and ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate (B) are taken as raw materials to prepare an olmesartan medoxomi I intermediate 1 (C) through condensation reaction; theolmesartan medoxomi I intermediate 1 (C) is subjected to hydrolysis in the presence of sodium hydroxide so as to obtain a compound (D); without separation, the compound (D) and raw material 4-Cloromethyl-5-methyl-1,3-dioxol-2-one (E) are directly subjected to condensation reaction so as to obtain an olmesartan medoxomi I intermediate 2 (F); and the olmesartan medoxomi I intermediate 2 (F) is subjected to deprotection in a 75% acetic acid aqueous solution so as to obtain olmesartan medoxomi I crude product, and acetone is adopted for recrystallization so as to obtain high purity olmesartan medoxomi I (G). The reaction conditions are mild; side products are few; the finished product purity is high; the preparation method is safe, is friendly to the environment, and is suitable for industrialized production; residual solvent is less; and quality standards are achieved.
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Paragraph 0015; 0031; 0032
(2018/09/08)
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- A olmesartan medoxomil and its preparation method (by machine translation)
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The invention discloses a olmesartan medoxomil and its preparation method, the present invention discloses a olmesartan medoxomil, its chemical structure is: The present invention novel method for preparation method, comprises the following steps: (1) preparing AMST - 3 C45 H44 N6 O3 ; (2) preparing C43 H39 N6 NaO3 AMST - 4; (3) preparing C48 H44 N6 O6 AMST - 6; (4) preparing olmesartan sha tanzhi thick; (5) to make the C29 H30 N6 O6 Olmesartan medoxomil. The invention separation effect is good, relatively low viscosity system, split-phase required time is short, the time is saved but also reduces energy consumption. Filtering and separating the high recovery rate, the product quality is high, the running cost is low; process without the need to add chemical, solvent solvent, not into the secondary pollution material; equipment and automatic operation, good stability, easy to realize industrial demand. (by machine translation)
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Paragraph 0028; 0032; 0033
(2017/11/16)
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- Preparation method of olmesartan medoxomil
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The invention provides an improved synthesis method of olmesartan medoxomil. The improved synthesis method comprises the following steps: enabling ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate and 4-[2-(triphenylmethyl tetrazole-5-yl)phenyl]phenylmethyl bromide to make alkylation reaction; after carrying out hydrolysis on an ester group, enabling a product and a 4-substituted methyl-5-methyl-2-oxo-1,3-dioxole derivative to make nucleophilic substitution reaction, so as to form ester; then removing the protection of triphenylmethyl to obtain the olmesartan medoxomil. According to the improved synthesis method provided by the invention, alkylation, hydrolysis, esterification and protective group removal reaction are finished through a one-pot method, and a separation and purification process is not needed. A few of instruments and equipment are needed and a technology is simple; the whole process only utilizes an organic solvent, so that industrial production is facilitated; filtering and desalting are used for replacing extraction and washing operation, so that a few of three wastes are generated, and the improved synthesis method is environmentally friendly.
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Paragraph 0043; 0044; 0045; 0046; 0047; 0048; 0049-0057
(2017/11/30)
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- A process for the preparation of olmesartan
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The invention relates to a method for preparing a medicine olmesartan medoxomil for treating hypertension, belongs to the field of medicines, and provides a method for preparing the olmesartan medoxomil with low material cost and mild reaction condition. The method comprises the following steps of: feeding two initial raw materials ( a compound 1 and a compound 2) according to a mole ratio of 1:1 during the process; adding the polyethylene glycol/N,N-dimethylacetamide composite catalyst to be completely reacted with the two initial raw materials so as to avoid a necessary impurity control process caused by excessive raw materials during classic reaction; and removing triphenylmethyl from a methanol/organic solvent mixed system to avoid participation of acid. Based on the improvement, the operation is greatly simplified, the cost is reduced, and the industrial production is facilitated.
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Paragraph 0015; 0026-0027
(2018/02/04)
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- Method for preparing olmesartan medoxomil
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The invention provides a method for preparing olmesartan medoxomil and belongs to the field of medicine synthesis. The method comprises the steps that imidazole monoester and 5-(4'-Bromomethyl-1,1'-biphenyl-2-yl)-1-triphenylmethyl-1H-tetrazole (BBTT) are used as starting materials and subjected to condensation, hydrolysis and acidification through a one-pot method in an acetone system to obtain 4-(1-hydroxyl-1-methylethyl)-2-propyl-{4-[2-(triphenylmethyl tetrazole-5-base) phenyl] phenyl} methylimidazole-5-carboxylic acid; the obtained product is then esterified with 4-chloromethyl-5-methyl-1,3-dioxole-2-ketone, wherein the purity of the esterified product through purification is larger than or equal to 99.5%; the esterified product is subjected to deprotection under the action of a 22.5% sulfuric acid solution to obtain highly purified olmesartan medoxomil. Condensation and esterification are performed through the one-pot method, so that the operation procedure is simplified, control is facilitated, the key intermediate esterified product is purified and then subjected to deprotection in the reaction, the olmesartan medoxomil with purity larger than or equal to 99.5% can be obtained, the total yield can reach 60%-75%, the raw materials are easy to obtain, cost is low, and the method is applicable to industrial production.
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Paragraph 0057; 0059
(2016/10/10)
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- A process for the preparation of olmesartan
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The invention discloses a preparation method of Olmesartan Medoxomil. The method is used for synthesizing an important intermediate 4-[2-(2-triphenylmethyl tetrazole-5-yl) phenyl] benzyl bromide (a compound III) so as to prepare the compound Olmesartan Medoxomil. The method is high in yield, easy to separate and purify, simple to operate and suitable for industrial production.
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Paragraph 0049-0050
(2017/04/19)
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- Improved synthesis process of olmesartan medoxomil derivatives
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The present invention relates to an improved olmesartan medoxomil derivative preparation method. More specifically, the olmesartan medoxomil derivative preparation method includes the steps of: initiating a coupling reaction between imidazole compounds and biphenyl methyl halide compounds; initiating a de-esterification reaction of the products of the coupling reaction; and initiating a condensation reaction between the de-esterified products with dioxolen derivatives. The present invention can optimize the reaction conditions of the coupling and de-esterification reactions to minimixe the content of the conventionally produced byproducts and residual solvent to significantly increase the yield and purity of the target products. The final olmesartan medoxomil derivatives obtained by using the method has the residual solvent content less than or equal to 500 ppm, thereby being lowered to 1/10 or less of the ICH guidelines.
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Paragraph 0059; 0060; 0094
(2016/12/22)
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- DEPROTECTION METHOD FOR TETRAZOLE COMPOUND
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The present invention relates to a method of deprotecting a tetrazole compound, useful as an intermediate for angiotensin II receptor blockers, and provides a novel production method of angiotensin II receptor blockers. Provided is a production method of a compound represented by the formula [3] or [4] or a salt thereof, including (i) reducing a compound represented by the formula [1] or [2] or a salt thereof in the presence of a metal catalyst and an alkaline earth metal salt, or (ii) reacting the compound with a particular amount of Br?nsted acid: wherein each symbol is as defined in the present specification.
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- METHOD FOR PRODUCING BIARYL COMPOUND
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Provided is a novel production method capable of producing a biaryl compound, which is useful as an intermediate for angiotensin II receptor blockers, economically under conditions suitable for industrial production. A production method of a biaryl compound of the formula [3] or a salt thereof, including reacting a 2-phenylazole derivative of the formula [1] or a salt thereof, with a benzene derivative of the formula [2] or a salt thereof in the presence of a metal catalyst, a base, and one or more kinds of compounds selected from the group consisting of (a) a monocarboxylic acid metal salt, (b) a dicarboxylic acid metal salt, (c) a sulfonic acid metal salt, and (d) a phosphate or phosphoric amide metal salt represented by RAxP(O)(OM)y wherein each symbol is as defined in the DESCRIPTION.
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Paragraph 0298-0300
(2015/07/15)
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- Discovery of olmesartan hexetil: A new potential prodrug of olmesartan
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Synthesis of a new ester prodrug of olmesartan, olmesartan hexetil (1), is described. It is in vitro stabilities and in vivo pharmacokinetics (PK) were evaluated. It showed high stability in simulated gastric juice, and was rapidly hydrolyzed to olmesartan in rat liver microsomes and rat plasma in vitro. C max and AUClast for olmesartan were significantly increased in case of hexetil prodrug, compared with olmesartan medoxomil. Olmesartan hexetil is proposed to be an efficient prodrug of olmesartan with markedly increased oral bioavailability.
- El-Gamal, Mohammed I.,Anbar, Hanan S.,Chung, Hye Jin,Kim, Hyun-Il,Cho, Young-Jin,Lee, Bong Sang,Lee, Sun Ahe,Moon, Ji Yun,Lee, Dong Jin,Kwon, Dow,Choi, Won-Jai,Jeon, Hong-Ryeol,Oh, Chang-Hyun
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p. 1347 - 1350
(2013/03/14)
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- PROCESS FOR OLMESARTAN MEDOXOMIL
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The present invention provides a process for the preparation of substantially pure trityl olmesartan medoxomil. The present invention also provides a process for purification of trityl olmesartan medoxomil. The present invention further provides a process for purification of olmesartan medoxomil.
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Page/Page column 9-10
(2012/01/14)
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- PROCESS FOR PREPARING OLMESARTAN MEDOXOMIL
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The invention relates to a process for preparing olmesartan medoxomil by the reaction of sodium 5-(1-hydroxy-1-methylethyl)-2-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylate, obtained by the reaction between ethyl 5-(1-hydroxy-1-methylethyl)-2-propyl-3H-imidazole-4- carboxylate from and 5-(4'-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole followed by saponification, with 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one, deprotection and purification.
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Page/Page column 17
(2012/05/19)
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- Design, synthesis, bioconversion, and pharmacokinetics evaluation of new ester prodrugs of olmesartan
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Synthesis of new ester prodrugs of olmesartan is described. Their in vitro stabilities in simulated gastric juice, rat plasma, and rat liver microsomes were tested. And the pharmacokinetic parameters for olmesartan after their oral administration were also estimated and compared with those in case of olmesartan medoxomil. Compounds 13 and 14 demonstrated high stability in simulated gastric juice and were rapidly metabolized to olmesartan in rat liver microsomes and rat plasma in vitro. In addition, Cmax and AUClast parameters were significantly increased in case of compounds 13 and 14 compared with olmesartan medoxomil. These results indicate that compounds 13 and 14 with cyclohexylcarboxyethyl and adamantylcarboxymethyl promoieties, respectively, are promising prodrugs of olmesartan with markedly increased oral bioavailability.
- Chang, Jeong-Soo,El-Gamal, Mohammed I.,Lee, Woong San,Anbar, Hanan S.,Chung, Hye Jin,Kim, Hyun-Il,Cho, Young-Jin,Lee, Bong Sang,Lee, Sun Ahe,Moon, Ji Yun,Lee, Dong Jin,Jeon, Hong-Ryeol,Lee, Jaehwi,Choi, Young Wook,Oh, Chang-Hyun
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experimental part
p. 3564 - 3569
(2011/11/12)
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- PREPARATION OF OLMESARTAN MEDOXOMIL
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Processes for preparing olmesartan medoxomil. In embodiments, processes for preparing olmesartan medoxomil do not require isolating one or more intermediate compounds.
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Page/Page column 11
(2011/02/24)
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- Novel amides and esters prodrugs of olmesartan: Synthesis, bioconversion, and pharmacokinetic evaluation
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Synthesis of novel amides and esters prodrugs of olmesartan is described. Their in vitro stability in rat plasma was tested. The results showed that the ester derivative IIa with n-octyl substituted dioxolone moiety was rapidly converted into olmesartan within 30 min. The pharmacokinetic parameters of IIa were studied and compared with those of olmesartan medoxomil. Compound IIa is proposed to be a promising prodrug of olmesartan.
- Park, Jin-Hun,Chang, Jeong-Soo,El-Gamal, Mohammed I.,Choi, Won-Kyoung,Lee, Woong San,Chung, Hye Jin,Kim, Hyun-Il,Cho, Young-Jin,Lee, Bong Sang,Jeon, Hong-Ryeol,Lee, Yong Sup,Choi, Young Wook,Lee, Jaehwi,Oh, Chang-Hyun
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scheme or table
p. 5895 - 5899
(2010/11/18)
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- PROCESS FOR THE PREPARATION OF OLMESARTAN MEDOXOMIL
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The present invention relates to an improved process for the manufacture of olmesartan and pharmaceutically acceptable salts and esters thereof as an active ingredient of a medicament for the treatment of hypertension and related diseases and conditions.
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Page/Page column 8
(2009/05/28)
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- PROCESS FOR THE PREPARATION OF OLMESARTAN MEDOXOMIL
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The present invention provides a process for the preparation of Olmesartan medoxomil] by condensing the ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate with 4-[2-(trityl tetrazol-5-yl)phenyl]benzyl bromide to obtain ethyl 4-(1-hydroxy-1-methyl ethyl)-2-propyl-1-{4-[2-(trityl tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate and then hydrolyzing ethyl 4-(1-hydroxy-1-methyl ethyl)-2-propyl-1-{4-[2-(trityl tetrazol-5-yl)phenyl]phenyl}methyl imidazole-5-carboxylate to obtain trityl Olmesartan dihydrate followed by reacting trityl Olmesartan dihydrate with 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene to obtain trityl Olmesartan medoxomil and then deprotecting trityl Olmesartan medoxomil to obtain Olmesartan medoxomil.
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Page/Page column 5
(2009/12/04)
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- A convenient and practical synthesis of olmesartan medoxomil methyl ether
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Synthesis of Olmesartan medoxomil methyl ether (2), a potential impurity of Olmesartan medoxomil (1), an angiotensin II receptor blockers is reported for the first time.
- Pati, Hari Narayan,Lahiri, Saswata,Sabbam, Ramesh Kumar,Vangala, Vijaya Bhaskar,Ramalingam, Boobalan,Hiriyanna, Salmara Ganeshbhat,Bose, Prosenjit
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p. 917 - 920
(2008/09/21)
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- PROCESS FOR PREPARING TRITYL OLMESARTAN MEDOXOMIL AND OLMESARTAN MEDOXOMIL
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A process for the preparation of trityl olmesartan comprising (a) condensing 4-(1-hydroxy- 1-methylethyl)-2-propyl-imidazol-5-carboxylic acid alkyl ester with trityl biphenyl bromide in the presence of a polar aprotic solvent and a base selected from the group consisting of alkali metal carbonates, alkali metal hydroxides, alkali metal alkoxides, and tertiary amines to obtain a compound of formula (V): b) deesterifying the compound of formula (V) with a base; and c) reacting the product of step (b) with 4-halomethyl-5-methyl-2-oxo-1,3-dioxolene of formula (IV): wherein X is halogen selected from F or Cl or Br or I, to obtain trityl olmesartan medoxomil of formula. The trityl olmesartan medoxomil may be deprotected to produce olmesartan medoxomil.
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Page/Page column 16
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF OLMESARTAN MEDOXOMIL
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The present invention relates to an improved process for the manufacture of olmesartan and pharmaceutically acceptable salts and esters thereof as an active ingredient of a medicament for the treatment of hypertension and related diseases and conditions.
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Page/Page column 5; 21
(2010/11/25)
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- Process for the preparation of olmesartan medoxomil
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The present invenion relates to an improved process for the manufacture of olmesartan and pharmaceutically acceptable salts and esters thereof as an active ingredient of a medicament for the treatment of hypertension and related diseases and conditions.
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Page/Page column 11-12
(2010/11/28)
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- A METHOD OF REMOVING THE TRIPHENYLMETHANE PROTECTING GROUP FROM PRECURSORS OF ANTIHYPERTENSIVE DRUGS
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A method of removing the triphenylmethane protecting group from precursors of antihypertensive drugs of general formula I, wherein R is a metabolically degradable group, B is a heterocyclic moiety with one or two 5- or 6-membered rings at least one of which contains two nitrogen heteroatoms, in which the compound of formula I is reacted with water in the presence of a solvent which is partially or completely miscible with water.
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Page/Page column 9
(2008/06/13)
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- ANGIOTENSIN II ANTAGONIST 1-BIPHENYLMETHYLIMIDAZOLE COMPOUNDS AND THEIR THERAPEUTIC USE
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Compounds of the following formula (I) or the formula (I) p : STR1 wherein R 1 is alkyl or alkenyl; R 2 and R 3 are hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, aryl, or aryl fused to cycloalkyl; R 4 is hydrogen, alkyl, alkanoyl, alkenoyl, arylcarbonyl, alkoxycarbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, tetrahydrofuryl, a group of formula--SiR a R b R c, in which R a, R b and R c are alkyl or aryl, alkoxymethyl, (alkoxyalkoxy)methyl, haloalkoxymethyl, aralkyl, aryl or alkanoyloxymethoxycarbonyl; R 5 is carboxy or--CONR 8 R 9, wherein R 8 and R 9 hydrogens or alkyl, or R 8 and R 9 together form alkylene; R 6 is hydrogen, alkyl, alkoxy or halogen; R. sup.7 is carboxy or tetrazol-5-yl; R p. sup.1 is hydrogen, alkyl, cycloalkyl or alkanoyl; R p 2 is a single bond, alkylene or alkylidene; R p 3 and R p 4 are each hydrogen or alkyl; R. sub.p 6 is carboxy or tetrazol-5-yl; and X p is oxygen or sulfur; and pharmaceutically acceptable salts and esters thereof. The compounds are AII receptor antagonists and thus have hypotensive activity and can be used for the treatment and prophylaxis of hypertension. The compounds may be prepared by reacting a biphenylmethyl compound with an imidazole compound.
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