- Improved synthesis of valsartan via nucleophilic aromatic substitution on aryloxazoline
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A highly efficient approach to the synthesis of the angiotensin II receptor antagonist valsartan (Diovan), one of the most important agents used in antihypertensive therapy today is described. The formation of the aryl-aryl bond represents the key step of its synthesis, which has been done by simple nucleophelic aromatic substitution on aryloxazoline with good yield and purity. Copyright Taylor & Francis Group, LLC.
- Ghosh, Samir,Kumar, A. Sanjeev,Soundararajan,Mehta
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Read Online
- Synthesis method of valsartan intermediate
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The invention relates to a synthesis method of a valsartan intermediate. The method comprises following steps: (1), a compound shown in the formula II is dissolved in an organic solvent firstly, an acid binding agent, sodium chloride or potassium chloride and water are added, the mixture is stirred uniformly, and a thermal insulation reaction is performed after valeryl chloride is dropwise added;(2), water is added for quenching after the reaction, alkaline washing, acid washing and alkaline washing are carried out in sequence, finally, a target product, namely, a compound shown in the formula I is obtained by reduced-pressure distillation, and the target product is N-[(2'-cyanobiphenyl-4-yl)methyl]-N-(1-oxopentyl)-L-valine methyl ester. According to the method, an appropriate amount of sodium chloride or potassium chloride is added to a reaction system, a hydrolysis reaction of valeryl chloride is inhibited by common-ion effect, so that the use amount of valeryl chloride is reduced,purity and yield of the product are increased, production cost is reduced, environmental pollution is reduced, and the method is more suitable for industrial production.
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Paragraph 0006; 0028-0039
(2019/09/17)
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- A method for preparing methyl valsartan
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The invention provides a preparation method of valsartan. The preparation method has the technical effects that amide methyl ester and sodium azide are used as raw materials and are catalyzed by amine salt to carry out tetrazole formation reaction; side effects are minimized by controlling the reaction course; main products are furthest generated; unreacted raw materials are recycled and reused; the yield in the preparation method is increased by more than 10% relative to the yields in existing processes; compared with the existing processes, the method has the effect that plenty of high-toxicity wastewater is no longer generated, and is easy to be widely popularized industrially.
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- A method of preparing the valsartan
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The invention discloses a method for preparing valsartan. The method comprises the following steps: carrying out a first-step reaction on L-valine methyl-ester hydrochloride and 2-cyan-4'-bromomethyl biphenyl, of which the molar ratio is (1-2):1; carrying out a second-step reaction together with pentanoyl chloride; finally carrying out a third-step reaction, so as to obtain a valsartan crude product, wherein the first-step reaction comprises the following steps: by taking acetonitrile as a reaction solvent, carrying out neutral reaction on the L-valine methyl-ester hydrochloride and potassium carbonate; then adding the 2-cyan-4'-bromomethyl biphenyl to react; adding the 2-cyan-4'-bromomethyl biphenyl by 2-6 times, wherein the reaction temperature is 50-65 DEG C; the reaction time is 3-7 hours. By adopting the method for preparing the valsartan, the quantity of byproducts corresponding to valsartan impurities T in the product in the first step is controlled, so as to control the quantity of the valsartan impurities T; furthermore, the other conditions are correspondingly adjusted; generation of other unmanageable impurities also can be avoided. Thus, the high-purity valsartan product can be prepared.
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Paragraph 0016; 0084; 0085; 0087
(2017/02/24)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF HYPERTENSION AND MANAGEMENT OF DIABETIC KIDNEY DISEASE
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The invention relates to the compounds of formula I and formula II or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I or formula II; and methods for treating or preventing hypertension and diabetic kidney disease may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of diabetes related renal complications, hypertension, albuminuria, Heart Diseases, ESRD, Kidney GFR complications, Vascular Disease, Ventricular Septal Defect, vascular dilation, high blood pressure, congestive heart failure (CHF), post-myocardial infarction (MI).
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Paragraph 0119; 0124; 0125; 0134; 0139; 0140
(2015/05/13)
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- Polymer-supported electron-rich oxime palladacycle as an efficient heterogeneous catalyst for the Suzuki coupling reaction
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Various electron-rich oxime palladacycle resins designed as heterogeneous catalysts were employed for the Suzuki coupling reaction of aryl halides with arylboronic acids. The electron-richness of the oxime ligand was controlled by the substituted alkoxy groups. Evaluation based on the electronic effect of the catalysts revealed that the alkoxy-substituted oxime palladacycle resins showed better catalytic activity than palladated Kaiser oxime resin in the Suzuki coupling reactions and that the catalytic activity of oxime palladacycle resins increased as the electron-richness of oxime ligand increased. The most electron-rich oxime palladacycle resin exhibited an excellent catalytic performance for the synthesis of both biaryl and heterobiaryl compounds, despite its heterogeneous system. As a practical application of the catalyst, a valsartan precursor was synthesized in high yield under mild conditions. The electron-rich oxime resin could also be reused for up to 5 cycles while maintaining good catalytic activity in the Suzuki coupling reaction.
- Cho, Hong-Jun,Jung, Sungwon,Kong, Saerom,Park, Sung-Jun,Lee, Sang-Myung,Lee, Yoon-Sik
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p. 1056 - 1064
(2014/04/03)
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- PROCESS FOR THE PREPARATION OF VALSARTAN
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The present invention relates to a process for the preparation of pure Valsartan (I) substantially free from impurities of formulae (Ia), (Ib), and (Ic), which comprises: (i) condensing 2-(4′-bromomethylphenyl)benzonitrile of formula (II) with L-valine methyl ester hydrochloride of formula (V) in the presence of a base in a solvent to produce N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester of formula (VI); (ii) treating the compound VI of step (i) with acid followed by treating with base to produce pure compound VI substantially free from dimeric impurity of formula (Via); (iii) reacting the pure compound of formula (VI) with n-valeryl chloride in the presence of a base to produce pure N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VII) substantially free from alkene impurity of formula (Vila); (iv) reacting the compound of formula (VII) with trialkyltin chloride and a metal azide in a solvent at a reflux temperature to produce N-(1-oxopentyl)-N-[[2′-(2-tributyltinte-trazol-5-yl)-(1,1′-biphenyl)-4-yl]methyl]-(L)-valine methyl ester of formula (VHIb) free from thermal degradation impurity (Villa); (v) hydrolyzing the compound of formula (VHIb) in the presence of alkaline conditions to produce Valsartan (I).
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- Synthesis and biological evaluation of novel potent angiotensin II receptor antagonists with anti-hypertension effect
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A series of novel angiotensin II type 1 receptor antagonists were prepared. Radioligand binding assay suggested that compounds 1b and 1c could be recognized by the AT1 receptor with an IC50 value of 1.6 ± 0.09 nM and 2.64 ± 0.7 nM, respectively. In vivo anti-hypertension experiments showed that compounds (1a, 1b, 1c, 1e) elicited a significant decrease in SBP and DBP of spontaneous hypertensive rats (SHRs). The antihypertensive effects maintained for 10 h, which indicated that these compounds had a favorable blood pressure-lowering effect. Acute toxicity testing suggested that the LD50 value of compound 1b was 2316.8 mg/kg which was lower than valsartan (LD50 = 307.50 mg/kg) but higher than losartan (LD50 = 2248 mg/kg). So they could be considered as novel anti-hypertension candidates and deserved for further investigation.
- Nie, Yong-Yan,Da, Ya-Jing,Zheng, Hao,Yang, Xiao-Xia,Jia, Lin,Wen, Cai-Hong,Liang, Li-Sha,Tian, Juan,Chen, Zhi-Long
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p. 2747 - 2761
(2012/05/20)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF VALSARTAN
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The present invention relates to a process for the preparation of pure Valsartan (I) substantially free from impurities of formulae (la), (lb), and (Ic), which comprises: (i) condensing 2-(4'-bromomethylphenyl)benzonitrile of formula (II) with L-valine methyl ester hydrochloride of formula (V) in the presence of a base in a solvent to produce N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester of formula (VI); (ii) treating the compound VI of step (i) with acid followed by treating with base to produce pure compound VI substantially free from dimeric impurity of formula (Via); (iii) reacting the pure compound of formula (VI) with n-valeryl chloride in the presence of a base to produce pure N-valeryl-N-[(2'-cyanobiphenyl-4-yl)methyl]- (L)-valine methyl ester (VII) substantially free from alkene impurity of formula (Vila); (iv) reacting the compound of formula (VII) with trialkyltin chloride and a metal azide in a solvent at a reflux temperature to produce N-(l-oxopentyl)-N-[[2'-(2- tributyltintetrazol-5-yl)-(l, l '-biphenyl)-4-yl]methyl]-(L)-valine methyl ester of formula (VHIb) free from thermal degradation impurity (Villa); (v) hydrolyzing the compound of formula (VHIb) in the presence of alkaline conditions to produce Valsartan (I).
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- AN IMPROVED PROCESS FOR THE PREPARATION OF N-PENTANOYL-N-[[2'-(1H-TETRAZOL-5-YI)[1,1'-BIPHENYL]-4-YI]METHYL]-L-VALINE
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Disclosed herein is an improved process for the preparation of pure N-Pentanoyl-N-[[2'- (1h-Tetrazol-5-Y1)[1,1'-Biphenyl]-4-Yl]Methyl]-L-Valine employing highly active carbon.
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- An efficient and telescopic process for valsartan, an angiotensin II Receptor Blocker
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An efficient, telescopic, and scalable process for an antihypertensive drug substance, valsartan with an overall yield of 58%, and ~99.9% purity is described. A simple, and safe process is developed for the recovery of tributyltin chloride from the tributyltin hydroxide, byproduct formed in the tetrazole ring construction, and reused in the synthesis of valsartan.
- Aalla, Sampath,Gilla, Goverdhan,Bojja, Yakambram,Anumula, Raghupathi Reddy,Vummenthala, Prabhakar Reddy,Padi, Pratap Reddy
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experimental part
p. 682 - 686
(2012/08/07)
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- NOVEL ZINC AZIDE COMPLEX AND A PROCESS FOR PREPARING TETRAZOLE DERIVATIVES USING THE SAME
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The present invention relates to a novel zinc azide complex. The present invention also relates to a process for preparing 5-substituted-1H-tetrazole derivatives from nitrile derivatives by using the zinc azide complex. According to the present invention, in particular, pharmaceutically active compounds for treating hypertension or intermediates useful for preparation thereof can be prepared effectively.
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Page/Page column 12
(2012/11/13)
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- IMPROVED PROCESS FOR PREPARING VALSARTAN
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The invention relates to an improved process for the preparation of valsartan wherein the cycloaddition reaction is performed is an ether as reaction solvent, with a metal salt azide and in the present of zinc halides.
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Page/Page column 16
(2011/10/31)
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- Process for the manufacture of organic compounds
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The present invention relates to a process for the manufacture of an angiotensin receptor blocker (ARB: also called angiotension II receptor antagonist or AT1 receptor antagonist) and salts, thereof, to novel intermediates and process steps.
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- PROCESS FOR THE MANUFACTURE OF ORGANIC COMPOUNDS
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The present invention relates to processes for the manufacture of an angiotensin receptor blocker (ARB; also called angiotension Il receptor antagonist or AT1 receptor antagonist) and salts thereof, to novel intermediates and process steps.
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Page/Page column 48-49
(2011/05/11)
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- Microwave-mediated synthesis of an arylboronate library
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A series of arylboronates has been synthesized from the reaction of 2-(2-, (3-, or (4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1{1-3} respectively with a range of N-, S-, and O-nucleophiles, using microwave-mediated chemistry. For the synthesis of N- and S-substituted boronates, a supported base, PS-NMM, was employed, and many reactions were complete within 15 min. With O-nucleophiles, a mixture of tetrabutylammonium bromide, potassium carbonate, and sodium hydroxide was employed. The resulting aminomethyl, mercaptomethyl, or alkoxy-/phenoxymethyl-arylboronates were subjected to microwave-mediated Suzuki Miyaura coupling reactions to afford a range of biaryls in moderate to good yields. The X-ray structures of five boronates were determined.
- Spencer, John,Baltus, Christine B.,Patel, Hiren,Press, Neil J.,Callear, Samantha K.,Male, Louise,Coles, Simon J.
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- Convenient synthesis of Valsartan via a Suzuki reaction
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An efficient synthesis of the angiotensin II inhibitor Valsartan (Diovan) is presented. The formation of the aryl-aryl bond represents the key step of its synthesis, which has been done by a Suzuki coupling of aryl boronate with 2-bromophenyl oxazoline with good yield and purity. This method overcomes many of the drawbacks associated with the previously reported syntheses.
- Ghosh, Samir,Kumar, A. Sanjeev,Mehta
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experimental part
p. 191 - 193
(2010/07/15)
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- PREPARATION OF VALSARTAN
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Processes for preparing valsartan and essentially amorphous valsartan are described.
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Page/Page column 15-17
(2010/08/18)
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- METHOD FOR ISOLATING 5-SUBSTITUTED TETRAZOLES
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The invention relates to a method for isolating 5-substituted tetrazoles of general formula (I) in which R represents a substituted biphenyl radical during which the ring closure, starting from a corresponding nitrile, is carried out in organic solvents while using alkali, alkaline-earth or organotin azides. The organic phases containing the nitrile and the tetrazol are firstly mixed with water while firstly forming three liquid phases, after which the aqueous phase containing the azide and the phase containing the nitrile are separated out, and the middle organic phase containing the tetrazol is subsequently processed. In the case of ester groups to be saponified, this phase is mixed with alkali lye, after which the organic phase is separated out and the aqueous phase is acidified or otherwise, this phase is immediately acidified and purified.
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Page/Page column 2-3
(2009/08/18)
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- Highly functionalised sulfur-based silica scavengers for the efficient removal of palladium species from active pharmaceutical ingredients
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The use of multidentate sulfur-based silica scavengers 1,2, and 3 as highly effective adsorbents for the removal of precious metals, specifically palladium residues in this paper, from highly functionalised synthetic intermediates and APIs is described. The synthesis and purification of the polar and electron-rich reaction products, containing multiple functional groups, from palladium-catalysed removals of commonly used protecting groups such as benzyl, benzyloxycarbonyl, and allyloxycarbonyl and Sonogashira, Suzuki, Heck, and Buchwald-Hartwig coupling reactions is reported. The significant levels of residual palladium species, typically associated with these reaction products, are successfully and rapidly removed to below acceptable regulatory levels, of less than 5 ppm, by simple, unoptimised treatment with the designed silica scavengers at room temperature. Performance aspects, including broad solvent compatibility, excellent stability, and high metal affinity, combined with large-scale availability, ease of handling, and minimal loss of API make these silica scavengers particularly useful to process development groups.
- Galaffu, Nicola,Man, Siud Pui,Wilkes, Robin D.,Wilson, John R. H.
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p. 406 - 413
(2012/12/31)
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- Synthesis of valsartan via decarboxylative biaryl coupling
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(Chemical Equation Presented) An efficient synthesis of the angiotensin II inhibitor valsartan (Diovan) is presented. Two routes were evaluated, both making use of an advanced version of our decarboxylative coupling for the construction of the biaryl moiety. Thus, in the presence of a catalyst system consisting of copper(II) oxide, 1,10-phenanthroline, and palladium(II) bromide, 2-cyanocarboxylic acid was coupled with 1-bromo(4-dimethoxymethyl)benzene in 80% yield and with 4-bromotoluene in 71% yield. The valsartan synthesis using 1-bromo(4-dimethoxymethyl)benzene was completed in four steps overall with a total yield of 39%, via a novel route that presents substantial economical and ecological advantages over the literature process, as it is more concise and stoichiometric amounts of expensive organometallic reagents are avoided.
- Goossen, Lukas J.,Melzer, Bettina
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p. 7473 - 7476
(2008/02/12)
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- Process for preparing Valsartan
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The invention relates to novel compound of formula (IV), which is an organic acid salt of N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine ester. This compound is an useful intermediate for process of preparation of Valsartan of formula (I), chemically known as (S)—N-(1-Carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine. This invention also relates to a process for preparing Valsartan using novel intermediate of formula (IV).
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Page/Page column 6-7
(2008/06/13)
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- Process for preparing valsartan
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A process for preparing valsartan.
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Page/Page column 4
(2008/06/13)
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- PROCESS FOR PREPARATION OF BIPHENYL TETRAZOLE
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The present invention relates to processes for the preparation of pure valsartan. Also provided is a barium salt of valsartan, and a pharmaceutical composition thereof.
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Page/Page column 10
(2008/06/13)
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- ACYL COMPOUNDS
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Compounds of the formula STR1 in which R 1 is an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen or hydroxyl, or a cycloaliphatic or araliphatic hydrocarbon radical; X 1 is CO, SO 2, or--O--C(=O)--with the carbon atom of the carbonyl group being attached to the nitrogen atom shown in formula I; X 2 is a divalent aliphatic hydrocarbon radical which is unsubstituted or substituted by hydroxyl, carboxyl, amino, guanidino or a cycloaliphatic or aromatic radical, or is a divalent cycloaliphatic hydrocarbon radical, it being possible for a carbon atom of the aliphatic hydrocarbon radical to be additionally bridged by a divalent aliphatic hydrocarbon radical; R. sub.2 is carboxyl which, if desired, is esterified or amidated, substituted or unsubstituted amino, formyl which, if desired, is acetalized, 1H-tetrazol-5-yl, pyridyl, hydroxyl which, if desired, is etherified, S(O) m--R where m is 0, 1 or 2 and R is hydrogen or an aliphatic hydrocarbon radical, alkanoyl, unsubstituted or N-substituted sulfamoyl or PO n H 2 where n is 2 or 3; X 3 is a divalent aliphatic hydrocarbon; R 3 is carboxyl, 5-tetrazolyl, SO. sub.3 H, PO. sub.2 H 2, PO 3 H 2 or haloalkylsulfamoyl; and the rings A and B independently of one another are substituted or unsubstituted; in free form or in salt form, can be prepared in a manner known per se and can be used, for example, as medicament active ingredients.
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