- Process for production of optically active pyrroloazepine derivatives
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It is provided a method for preparing the pyrroloazepine derivatives, especially in optically active form useful as drugs, by low-priced and simple method and in industrial applicable scale, represented by the following formula (I): wherein Z represents optionally substituted phenyl group, which comprises; a process for the asymmetric reduction of ketone compound with metal hydride compound and alcohol compound in the presence of optically active cobalt complex catalyst, and a process for the purification of the resulting compound.
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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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- 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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- 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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