As an efficient and enantioselective synthesis of the 4,5-dihydroxy-benzazepine compounds, the syntheses of optically active 5-0-protected trans-4,5-dihydroxybenzazepine derivatives were accomplished. The trans-7-chloro-4-hydroxy-5-methoxymethoxy-1 -(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine [(±)-4] was kinetically resolved by lipase-catalyzed transesterification. The optically active 4* was isomerized into the cis compound (6*) utilizing the Mitsunobu esterification followed by hydrolysis. The chiral compounds (4* and 6*) were converted to the 4,5-bismethoxymethoxy compounds (7*-10*), which were the intermediates for the compounds (2a, b and 3a, b).

The unstable 2-pyrrolidinol derivative (2), as a metabolite of a new vasopressin V-2 receptor agonist OPC-51803 (1), was synthesized by the cytochrome P-450 model reaction of 1 with the Fe-salen complex and iodosobenzene.

An efficient and enantioselective synthesis of (R)-[1-(p-toluene-sulfonyl)-2,3,4,5-tetrahydro- 1H-1-benzazepin-5-yl]acetic acid (2), a key intermediate in the synthesis of (R)-2-{1-[2-chloro-4-(1-pyrrolidinyl)benzoyl]- 2,3,4,5- tetrahydro-1H-1-benzazepin-5-yl}-N-isopropylacetamide (OPC-51803, 1), was accomplished. The chiral alcohol [(S)-3], the precursor of (R)-2, was separated from the racemic alcohol [(+/-)-3] using the lipase mediated transesterification in vinyl acetate. The obtained (S)-3 was fractionated without using column chromatography and it was converted to 2 without a decrease in the enantiomeric excess.

The optically active enantiomers of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl] -2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061, 1) were enantioselectively synthesized. The chiral acetate ((R)-(-)-3) and the chiral alcohol ((S)-(+)-2) were prepared via the resolution of the racemic alcohol ((+/-)-2) using the lipase-mediated transesterification with vinyl acetate. Compounds ((R)-(-)-3) and ((S)-(+)-2) were converted to optically active 1.

The optical isomers of 5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-31260, 1) and its metabolites (2, 3, 4, 5 and 6) were enantioselectively synthesized. The chiral acetate 8b and alcohol 7a were prepared via the resolution of the racemic alcohol (±)-7 using the lipase-mediated transesterification in vinyl acetate. The compounds 8b and 7a were converted to the hydroxy metabolites (2a and 2b), the methylamine metabolites (3a and 3b), the dimethylamines (1a and 1b), and the amine metabolites (4a and 4b) in several steps while maintaining their absolute configurations. The 4,5-diol metabolites (5a, 5b, 6a and 6b) were synthesized from the key intermediates obtained by the lipase-catalyzed transesterification.

The metabolism of olanexidine [1-(3,4-dichlorobenzyl)-5-octylbiguanide], a new potent biguanide antiseptic, was investigated in dog liver microsomes to characterize the enzyme(s) catalyzing the biotransformation of olanexidine to C-C bond cleavage metabolites. Olanexidine was initially biotransformed to monohydroxylated metabolite 2-octanol (DM-215), and DM-215 was subsequently oxidized to diol derivatives threo-2,3-octandiol (DM-221) and erythro-2,3-octandiol (DM-222). Diols were further biotransformed to a ketol derivative and C-C bond cleavage metabolite (DM-210, hexanoic acid derivative), an in vivo end product, in the incubation with dog liver microsomes. The formations of DM-215, DM-221, DM-222, and DM-210 followed Michaelis-Menten kinetics, and Eadie-Hofstee analysis of the metabolite formation activity confirmed single-enzyme Michaelis-Menten kinetics. The K(m) and V(max) values for the formation of DM-210 appeared to be 2.42 microM and 26.6 pmol/min/mg in the oxidation of DM-221 and 2.48 microM and 30.2 pmol/min/mg in the oxidation of DM-222. The intrinsic clearance (V(max)/K(m)) of the C-C bond cleavage reactions was essentially the same with either DM-221 or DM-222 as substrate. These oxidative reactions were significantly inhibited by quinidine, a selective inhibitor of CYP2D subfamilies, indicating the metabolic C-C bond cleavage of the octyl side chain of olanexidine to likely be mediated via the CYP2D subfamily in dog liver microsomes. This aliphatic C-C bond cleavage by cytochrome P450s may play an important role in the metabolism of other drugs or endogenous compounds possessing aliphatic chains.

(R)-2'-Hydroxy-1,1'-binaphthalene-2-yl benzoate (1a) was found to be an efficient asymmetric acylating agent for a secondary alcohol, 5-hydroxy-2,3,4,5-tetrahydro-1-(p-toulenesulfonyl)-1H-benzazepine (2a), which is a key intermediate for preparing a metabolite of the vasopressin V-2 receptor antagonist, OPC-31260 (4).

The metabolism of 1-(3,4-dichlorobenzyl)-5-octylbiguanide (OPB-2045), a new potent biguanide antiseptic, was investigated using rat and dog liver preparations to elucidate the mechanism of OPB-2045 metabolite formation, in which the octyl side chain is reduced to four, five, or six carbon atoms. Chemical structures of metabolites were characterized by 1H NMR, fast atom bombardment/mass spectrometry, and liquid chromatography/electrospray ionization-tandem mass spectrometry. Three main metabolites were observed during incubation of OPB-2045 with rat liver S9: 2-octanol (M-1), 3-octanol (M-2), and 4-octanol (M-3). In the incubation of OPB-2045 with dog liver S9, eight metabolites were observed, seven of which being M-1, M-2, M-3, 2-octanone (M-4), threo-2,3-octandiol (M-5), erythro-2,3-octandiol (M-6), and 1,2-octandiol (M-7). M-5 and M-6 were further biotransformed to a ketol derivative and C-C bond cleavage metabolite (hexanoic acid derivative), an in vivo end product, in the incubation with dog liver microsomes. The reactions required NADPH as a cofactor and were significantly inhibited by the various inhibitors of cytochrome P450 (i.e., CO, n-octylamine, SKF 525-A, metyrapone, and alpha-naphthoflavone). The results indicate that the degraded products of OPB-2045 are produced by C-C bond cleavage after monohydroxylation, dihydroxylation, and ketol formation at the site of the octyl side chain with possible involvement of cytochrome P450 systems. This aliphatic C-C bond cleavage by sequential oxidative reactions may play an important role in the metabolism of other drugs or endogenous compounds that possess aliphatic chains.

The optically active metabolites of (S)-3,4-dihydro-6-[3-(1-o-tolyl-2-imidazolyl)sulfinyl-propoxy]-2(1H)-quinolinone (OPC-29030, 1), which is a new anti-platelet agent (platelet adhesion inhibitor), were effectively synthesized by the enzyme-catalyzed enantioselective transesterification of the racemic sulfinyl metabolites. The enzymes can recognize a stereogenic sulfur atom remote from the reaction site.

1. The biotransformation of 1-(3,4-dichlorobenzyl)-5-octylbiguanide (OPB-2045), a new potent biguanide antiseptic, was investigated in male beagle dogs. Urinary and faecal excretion of unchanged compound and metabolites were studied following a single subcutaneous injection of 14C-labeled compound at a dose of 1 mg/kg. 2. Four urinary metabolites were structually identified using synthetic standards and/or spectral data as 3,4-dichlorobenzoic acid, 6-[5-(3,4-dichlorobenzyl)-1-biguanidino] hexanoic acid (DM-210), 4-[5-(3,4-dichlorobenzl)-1-biguanidino] butanoic acid (DM-212) and 5-[5-(3,4-dichlorobenzyl)-1-biguanidino] pentanoic acid (DM-213). 3. The predominant radioactive substances in the excreta were DM-213 and DM-210 at 26.1% and 25.5%, respectively, of the dose. No unchanged compound was detected in the urine, and in the faeces it was only 2% of the dose.

A metabolite of Aripiprazole (1), 7-[4-[4-(2,3-dichloro-4-hydroxyphenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone (2), was prepared by the coupling reaction of 1-(4-benzyloxy-2,3-dichlorophenyl)-piperazine (11) with 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone (16). The palladium-catalyzed amination of contiguous tri- and tetra-substituted benzenes with piperazine derivatives was investigated. The key intermediate 11 was efficiently prepared using the palladium-catalyzed amination of phenyl bromide 15 with piperazine.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A hydroxylated metabolite (5a) of 7-hydroxy-1-[[[4-(3-methoxyphenyl)-1-piperazinyl]acetyl]amino]-2, 2, 4, 6-tetramethylindan (OPC-14117), which is a novel cerebroprotective agent with central nervous system-stimulating activity, was synthesized by use of a model cytochrome P-450 system. In order to confirm the structure of this compound it was prepared by another route. The structures of several metabolites (5a, 7 and 8) were identified by means of comparisons with the synthetic compounds.

Optically active 2-[(3-hydroxypropyl)sulfinyl]-1-(o-tolyl) (S)-2 was synthesized by kinetic resolution of (+/-)-2 with lipase and hydrolysis of the acetate (S)-3 with potassium carbonate. The reaction mixture of the lipase-catalyzed transesterification was converted to the phthalic acid derivative (R)-4, and this (R)-4 and the unreacted acetate (S)-3 were fractionated without use of column chromatography. The unrequired recovered alcohol (R)-2 was also racemized and (+/-)-2 was repeatedly submitted to the lipase-catalyzed transesterification. (C) 1997 Elsevier Science Ltd.

The metabolism of toborinone, (+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-quin - olinone, a novel inotropic agent, was studied in rats and dogs after intravenous administration. Chemical structures of the 13 metabolites were characterized by direct-probe FAB/MS and field desorption/MS, LC/FAB/MS, and various NMR measurements. After intravenous dosing of 10 mg/kg [14C]toborinone, fecal and urinary recoveries of the 14C dose were approximately 70% and 26-30%, respectively, in both rats and dogs. The predominant component of radioactivity was the unchanged toborinone in every biological specimen in rats and dogs. Although unchanged toborinone was predominantly observed, toborinone underwent extensive conjugations with glucuronic acid, sulfate, and glutathione, either directly or following phase I reaction. Metabolites resulting from oxidative N-C cleavage were minor both in number and in quantity in every biological specimen in rats and dogs. In rats, toborinone underwent O-demethylation to form M-7 and successive phase it reaction to yield the glucuronide M-1 and the sulfoconjugate M-2, and deconjugation to yield M-7, which was a primary metabolite accounted for 35.67% of the radioactivity excreted in the feces by 48 hr. Conjugates M-1 and M-2 were the major metabolites in rat plasma. In dogs, toborinone was metabolized via mercapturic acid pathway to yield the primary metabolites, cysteine conjugates M-10 and M-11 that accounted for 19.10% and 6.70% of the radioactivity excreted in the feces by 48 hr and that were detected species specifically in dogs. The glutathione conjugate M-13, which was isolated from in vitro incubations using dog liver, led us to consider a possible mercapturic acid pathway from the parent compound to M-10. Metabolites in dog plasma and those in urine in both rats and dogs were minor in quantity. The metabolic pathways of toborinone in rats and dogs are proposed herein.

Objectives: To determine human cytochrome P450 isoform(s) (CYPs) involved in the metabolism of carteolol, the biotransformation of the compound was investigated in vitro using ten isoforms of human cytochrome P450 expressed in human AHH-1 TK ± cell lines. In addition, the inhibitory effects of carteolol on the activities of important CYP isoforms, namely, CYP1A2, 2C9, 2C19, 2E1, and 3A4, were examined.

The absolute configuration of enantiomers of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid [(+/-)-1, rebamipide] was assigned. The key intermediate, (S)-quinoline derivative [(S)-3], was prepared by palladium-catalyzed coupling reaction of 4-iodoquinoline with organozinc compound. This quinolinylalanine derivative was also synthesized from alpha-amino acid derivative of 2(1H)-quinolinone [(+)-4], which was able to convert into optically active rebamipide. Therefore the absolute configuration of (+)- and (-)-rebamipide was found to be R and S, respectively.

The metabolites of 1-[1-[4-(3-acetylaminopropoxy)benzoyl]piperid-yl]-3,4-dihydro-2(1H)-quinolinone (OPC-21268, 1), vasopressin V-1 receptor antagonist were synthesized to confirm the proposed structures and to examine their vasopressin V-1 receptor antagonistic activity. The structures of metabolites (2a - 6) were identified by means of comparison with synthetic compounds. The activity of the metabolites was found to be lower than that of 1.

A novel series of N-acylamino acid analogues of 2(1H)-quinolinone was synthesized and evaluated for antiulcer activity against acetic acid-induced gastric ulcer in rats. Out of this investigation, 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid (rebamipide, OPC-12759) was identified. The structure-activity relationships are discussed.Rebamipide did not only increase the healing rate of a chronic gastric ulcer model, acetic acid-induced gastric ulcer in rats, but also prevented recurrence and/or relapse of the ulcer in long term observation. Rebamipide inhibited the formation of gastric mucosal lesions induced by various conditions, Rebamipide did not inhibit gastric acid secretion, although it potentiated gastric mucosal defensive factors such as mucus secretion, alkaline secretion, gastric mucosal bloodflow and mucosal barrier. Rebamipide inhibited ethanol-induced gastric mucosal necrosis, which was completely abolished by pretreatment with indomethacin, suggesting the mucosal protective effect is associated with endogenous prostaglandins. Rebamipide inhibited production of superoxide from polymorphonuclear leukocytes and scavenged hydroxyl radical in vitro. Rebamipide showed useful efficacy on Helicobacter pylori-induced cell damage associated with activated neutrophils.The enantiomers of rebamipide were synthesized by using three efficient methods. Both enantiomers showed anti-ulcer activity against, acetic acid-induced gastric ulcer and EtOH-induced gastric ulcer. The pair of enantiomers showed a small difference in activity.