- Catalyst-Controlled Chemodivergent Reactions of 2-Pyrrolyl-α-diazo-β-ketoesters and Enol Ethers: Synthesis of 1,2-Dihydrofuran Acetals and Highly Substituted Indoles
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A catalyst-controlled, chemodivergent reaction of pyrrolyl-α-diazo-β-ketoesters with enol ethers is reported. While Cu(II) catalysts selectively promoted a [3 + 2] cycloaddition to provide pyrrolyl-substituted 2,3-dihydrofuran (DHF) acetals, dimeric Rh(II) catalysts afforded 6-hydroxyindole-7-carboxylates via an unreported [4 + 2] benzannulation. The choice of enol ether proved to be crucial in determining both regioselectivity and yield of the respective products (up to 91% yield for Cu(II) and 82% for Rh(II) catalysis). Furthermore, the DHF acetals were shown to serve as precursors to 7-hydroxyindole-6-carboxylates (isomeric to the indoles formed from Rh) and highly substituted furans in the presence of Lewis acids. Thus, from a common pyrrolyl-α-diazo-β-ketoester, up to three unique heterocyclic scaffolds can be achieved based on catalyst selection.
- France, Stefan,Guerra Faura, Gabriel,Nguyen, Tena
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supporting information
p. 10088 - 10104
(2021/07/31)
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- Successive Pd-Catalyzed Decarboxylative Cross-Couplings for the Modular Synthesis of Non-Symmetric Di-Aryl-Substituted Thiophenes
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Oligothiophenes are important organic molecules in a number of burgeoning industries as semi-conducting materials due to their extensive π-conjugation and charge transport properties. Typically, non-symmetric, di-aryl-substituted thiophenes are prepared by the successive formation of Grignards, organotin, and/or boronic acid intermediates that can be subsequently employed in cross-coupling reactions. While reliable, these approaches present synthetic difficulties due to the reactivity of organo-metallic/pseudo-metallic species, and produce considerable amounts of waste due to necessary pre-functionalization. We have developed a decarboxylative cross-coupling route as an effective strategy for the modular and less wasteful synthesis of a wide range of non-symmetric, di-arylthiophenes. This method uses a thiophene ester building block for successive decarboxylative palladium-catalyzed couplings that allows for the efficient synthesis and evaluation of the opto-electronic properties of a library of candidate semi-conductors with functional groups that could be challenging to access using previous routes.
- Douglas, Liam Z.,Forgione, Pat,Liu, Jiang Tian,Messina, Cynthia
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supporting information
(2020/08/17)
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- Carboxylation of indoles and pyrroles with CO2 in the presence of dialkylaluminum halides
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The Lewis acid-mediated carboxylation of arenes with CO2 has been successfully applied to 1-substituted indoles and pyrroles by using dialkylaluminum chlorides instead of aluminum trihalides. Thus, the carboxylation of 1-methylindoles, 1-benzyl-, and 1-phenylpyrroles proceeds regioselectively with the aid of an equimolar amount of Me2AlCl under CO2 pressure (3.0 MPa) at room temperature to afford the corresponding indole-3-carboxylic acids and pyrrole-2-carboxylic acids in 61-85% yields, while the same treatment of 1,2,5-trimethylpyrrole affords the 3-carboxylic acid in 52% yield.
- Nemoto, Koji,Onozawa, Satoru,Egusa, Naoki,Morohashi, Naoya,Hattori, Tetsutaro
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experimental part
p. 4512 - 4514
(2009/11/30)
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- Synthesis and biological evaluation of enantiomerically pure pyrrolyloxazolidinones as a new class of potent and selective monoamine oxidase type A inhibitors
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Due to the key role played by monoamine oxidases (MAOs) in the metabolism of neurotransmitters, MAO inhibitors (MAOIs) represent an useful tool for the treatment of several neurological diseases. Among selective MAOIs, MAO-A inhibitors (e.g. clorgyline) are used as antidepressant and antianxiety drugs and are claimed to protect neuronal cells against apoptosis, and selective MAO-B inhibitors (e.g. L-deprenyl) can be used in the treatment of Parkinson's disease either alone or in combination with L-DOPA. However, they engender covalent bonds with the active site of the enzyme and induce irreversible inhibition; moreover, they tend to lose their initial selectivity at high dosages or with repeated administrations. Phenyloxazolidinones belong to third-generation-MAOIs, characterized by a selective and reversible inhibition of the enzyme. Among these molecules, the most representative are toloxatone and befloxatone, two selective and reversible MAO-A inhibitors used in therapy as antidepressant drugs. Going on our searches on CNS potentially active compounds containing a pyrrole moiety we prepared 3-(1H-pyrrol-1-yl)-2-oxazolidinones (1) and isomeric 3-(1H-pyrrol-2-and -3-yl)-2-oxazolidinones (2 and 3) as anti-MAO agents. Such derivatives resulted selective and reversible MAO-A inhibitors. The most potent compound is (R)-5-methoxymethyl-3-(1H-pyrrol-1-yl)-2-oxazolidinone (1b), endowed with very high potency (KiMAO-A=4.9 nM) and A-selectivity (A-selectivity=10,200, about 116-fold greater than that of befloxatone).
- Mai,Artico, Marino,Esposito,Ragno,Sbardella,Massa
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p. 231 - 241
(2007/10/03)
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- Pyrroloazepine derivatives
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A method for treating a circulatory disease or condition in a mammal, which entails administering to the mammal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof: wherein the ring P represented by ?is a pyrrole ring having the following structure: wherein R1represents C1-C8alkyl, C3-C8cycloalkyl, C4-C8cycloalkyl-alkyl, C6-C14aryl or C7-C22aralkyl, which are optionally substituted; and R2represents H or C1-C8alkyl, which is optionally substituted; the dashed line indicates the presence or absence of a bond; and, when the bond is present, Z2is not present and Z1represents H, but, when the bond is absent, Z1and Z2are both H; Z1represents H and Z2represents a group OR3, in which R3represents H, C1-C8alkyl, or C7-C22aralkyl, which are optionally substituted; Z1and Z2both represent groups SR4, in which R4represents C1-C8alkyl or C7-C22aralkyl, which are optionally substituted; or Z1and Z2are combined together to represent O, a group NOR5, in which R5represents H, or C1-C8alkyl or C2-C3alkylenedithio, which are optionally substituted; A represents alkylene, alkenylene or alkynylene; and Y represents a group in which W is CH, C═ or N, m is for 0 or 1, n is for 1, 2 or 3, G is O, S, C═O, sulfinyl, sulfonyl, alkylene, alkenylene or acetal; E1and E2is H or C1-C8alkyl; and D represents an aromatic hydrocarbon or an aromatic heterocyclic ring. The compound (I) has strong serotonin-2 receptor antagonistic action and low toxicity and less side effects, and is therapeutically useful in the treatment of circulatory diseases and/or conditions related thereto.
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- Intermittent claudication therapeutic drugs comprising pyrroloazepines
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A method of treating or improving intermittent claudication, which comprises administering, to a patient with intermittent claudication, a pyrroloazepine derivative or a pharmacologically acceptable salt thereof, said pyrroloazepine derivative being represented by the following formula (I): wherein the dotted line indicates existence or nonexistence of a bond; when the bond of the dotted line exists, X does not exist, and, when the bond of the dotted line does not exist, X represents a hydrogen atom, a hydroxy group or a group OR1in which R1represents a substituted or unsubstituted alkyl group; Y represents a linear or branched, substituted or unsubstituted alkyl group; Z1and Z2are the same or different and each independently represent a hydrogen atom, a hydroxy group or a halogen atom; and W represents a hydrogen atom or a methyl group.
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- Synthesis and serotonin 2 (5-HT2) receptor antagonist activity of 5- aminoalkyl-substituted pyrrolo [3,2-c]azepines and related compounds
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A series of 5-aminoalkylpyrrolo[3,2,c]azepine derivatives was synthesized and their serotonin 2 (5-HT2) receptor antagonist and antiplatelet aggregation activities were evaluated. 5-HT2 receptor antagonist activity was largely determined by the nature of the substituent at the 8-position as well as the aminoalkyl group at the 5-position of the pyrrolo[3,2-c]azepine ring. Compound 18a, 5-[3-[4-(4-(4- fluorophenyl)piperazin-1-yl]propyl]-8-hydroxy-1-methyl-1,4,5,6,7,8- hexahydropyrrolo[3,2-c]azepin-4-one, was recognized as having potent 5-HT2 receptor antagonist activity with weak α1 adrenoceptor blocking activity and no significant D2 receptor binding affinity, while the corresponding isomeric pyrrolo[3,4-c]azepine derivative (22) displayed only weak 5-HT2 receptor antagonist activity. After racemic 18a was resolved directly via diastereomeric salt formation, each enantiomer was evaluated precisely. The 5-HT2 receptor antagonist activity of 18a was found to reside primarily in (-)-18a (which was about 14-fold more potent than (+)-18a in isolated guinea pig arteries). Consequently, (S)-(-)-18a (SUN C5174)displayed the overall best profile with potent 5-HT2 receptor antagonist activity (pA2 = 8.98 ± 0.06) and high selectivity versus other receptors. SUN C5174 showed a marked inhibitory effect on the platelet aggregation induced by serotonin in combination with collagen and adenosine diphosphate (ADP) in canine or human platelet-rich plasma (IC50 = 6.5 to 16 nM). Moreover, this compound significantly inhibited the mortality rate in mouse acute pulmonary thromboembolitic death induced by collagen and serotonin at oral doses of 0.3 mg/kg or higher. SUN C5174 is currently undergoing clinical evaluation.
- Mizuno, Akira,Ogata, Atsuto,Kamei, Tomoe,Shibata, Makoto,Shimamoto, Tetsuo,Hayashi, Yasuhiro,Nakanishi, Kyoko,Takiguchi, Chikako,Oka, Naomi,Inomata, Norio
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p. 623 - 635
(2007/10/03)
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- Pyrroloazepine derivatives
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A pyrroloazepine compound having the following formula (I): wherein the ring P represented by STR1 is a pyrrole ring having the following structure: STR2 wherein R1 represents C1 -C8 alkyl, C3 -C8 cycloalkyl, C4 -C8 cycloalkyl-alkyl, C6 -C14 aryl or C7 -C22 aralkyl, which are optionally substituted; and R2 represents H or C1 -C8 alkyl, which is optionally substituted; the dashed line indicates the presence or absence of a bond; and, when the bond is present, Z2 is not present and Z1 represents H, but, when the bond is absent, Z1 and Z2 are both H; Z1 represents H and Z2 represents a group OR3, in which R3 represents H, C1 -C8 alkyl, or C7 -C22 aralkyl, which are optionally substituted; Z1 and Z2 both represent groups SR4, in which R4 represents C1 -C8 alkyl or C7 -C22 aralkyl, which are optionally substituted; or Z1 and Z2 are combined together to represent O, a group NOR5, in which R5 represents H, or C1 -C8 alkyl or C2 -C3 alkylenedithio, which are optionally substituted; A represents alkylene, alkenylene or alkynylene; and Y represents a group in which W is CH, C= or N, m is for 0 or 1, n is for 1, 2 or 3, G is O, S, C=O, sulfinyl, sulfonyl, alkylene, alkenylene or acetal; E1 and E2 is H or C1 -C8 alkyl; and D represents an aromatic hydrocarbon or an aromatic heterocyclic ring. The compound (I) has strong serotonin-2 receptor antagonistic action and low toxicity and less side effects, and is therapeutically useful in the treatment of circulatory diseases and/or conditions related thereto.
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