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An efficient large-scale synthesis of Esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (1), a new antirheumatic drug, was established. A small amount of water increased the yield of the Michael addition of thioacetic acid (4) to 2-methylene-4-(4-methylphenyl)-4-oxobutanoic acid (2) to give 1. Multikilogram amounts of 1 (over 25 kg) were successfully obtained using this procedure. In addition, this procedure was repeated nine times, and reproducible results were obtained. See Ref. [1]

A series of 8'-substituted N-(endo-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1, 2-dihydro-3-quinolinecarboxamides were synthesized. The 5-HT4 receptor agonistic activity was evaluated using the isolated guinea pig ileum preparation. Of the compounds synthesized, N-(endo-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1, 2-dihydro-3-quinolinecarboxamide (15a, TS-951) exhibited the most potent serotonin 5-HT4 receptor agonistic activity. This compound had a high affinity for the serotonin 5-HT4 receptor althought it had no affinities for other broad spectrum receptors. Furthermore, it remarkably enhanced gastrointestinal motility in conscious fed dogs without unfavorable effects that non-selective serotonin 5-HT4 receptor agonist has. TS-951 may be useful in improving gastrointestinal dysfunction.

Highly functionalized, unsymmetrical disulfides (presumed metabolites of a bioactive sulfide) were synthesized by a base-induced, crossed reaction of two different symmetrical disulfides. The reaction was also applied to the preparation of a vitamin B1 derivative, Prosultiamine.

A series of 8'-substituted N-(endo-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1, 2-dihydro-3-quinolinecarboxamides were synthesized. The 5-HT4 receptor agonistic activity was evaluated using the isolated guinea pig ileum preparation. Of the compounds synthesized, N-(endo-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1, 2-dihydro-3-quinolinecarboxamide (15a, TS-951) exhibited the most potent serotonin 5-HT4 receptor agonistic activity. This compound had a high affinity for the serotonin 5-HT4 receptor althought it had no affinities for other broad spectrum receptors. Furthermore, it remarkably enhanced gastrointestinal motility in conscious fed dogs without unfavorable effects that non-selective serotonin 5-HT4 receptor agonist has. TS-951 may be useful in improving gastrointestinal dysfunction.

An efficient and practical procedure for the synthesis of esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (1), a new antirheumatic drug, has been developed. The intermediate, 2-methylene-4-(4-methylphenyl)-4-oxobutanoic acid (2), was prepared by Friedel-Crafts acylation of toluene with itaconic anhydride (3) in the presence of aluminum trichloride and nitrobenzene in 63% yield without silica gel column purification. Compound 1 was prepared by Michael addition of 2 with thioacetic acid (4) in 74% yield. Overall, 1 was obtained in 47% yield from 3. The structures and synthetic mechanisms of by-products (five compounds) of 2 were also clarified.

We have developed esonarimod, (+/-)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid, as a new antirheumatic drug. Now we describe herein the preparation of the enantiomers of (+/-)-deacetylesonarimod, the pharmaceutically active metabolites of esonarimod, and comparison of their antirheumatic activities. No significant difference has been observed between the two enantiomers. In a pre-clinical study of esonarimod, other metabolites were detected in rat blood or urine. We also synthesized these compounds as authentic samples to analyze the human metabolites in clinical studies of esonarimod.

A series of N-azabicycloalkyl-1-alkyl-2-oxo-1, 2-dihydro-3-quinolinecarboxamides were synthesized and tested for serotonin 5-HT4 receptor-stimulating effects in the regulation of electrically-evoked contraction in guinea pig muscle. Among them, N-azabicycloalkyl-1-isopropyl-2-oxo-1, 2-dihydro-3-quinolinecarboxamide (8c, 9c, 10c, 11c, 12c) exhibited potent serotonin 5-HT4 receptor-stimulating activity. The most potent compound, N-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1, 2-dihydro-3-quinolinecarboxamide (8c, ED50=36.3 nM), was seven times as active as cisapride, while 8c had no affinity for 5-HT1A, 5-HT1D, D2, muscarinic M2 or muscarinic M3 receptors even at 10μM. Compound 8c stimulated digestive tract motility in conscious fed dogs (1.0 mg/kg p.o.).

A series of N-azabicycloalkyl-1-alkyl-2-oxo-1,2-dihydro-3-quinolinecarboxamides were synthesized and tested for serotonin 5-HT4 receptor-stimulating effects in the regulation of electrically-evoked contraction in guinea pig muscle. Among them, N-azabicycloalkyl-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (8c, 9c, 10c, 11c, 12c) exhibited potent serotonin 5-HT4 receptor-stimulating activity. The most potent compound, N-(endo-8-methyl-8-azabicyclo[3.2.1 oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (8c, ED50 = 36.3 nMi), was seven times as active as cisapride, while 8c had no affinity for 5-HT1A, 5-HT1D, D2, muscarinic M2 or muscarinic M3 receptors even at 10 microM. Compound 8c stimulated digestive tract motility in conscious fed dogs (1.0 mg/kg p.o.).

IT-066 (3-amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]- cis -2-butenylamino]-3-cyclobutene-1,2-dione hydrochloride), an H 2 -receptor antagonist, shows highly potent, time-dependent, and irreversible antagonism at H 2 -receptors. We identified the structurally important parts of IT-066 involved in its interaction with the H 2 -receptor, and explored its unique mode of action by investigating the H 2 -receptor blocking action of IT-066 and related compounds in guinea pig isolated atria. IT-066 is structurally divided into three different parts: a tertiary amine and hydrophobic group, a connecting carbon chain, and a polar group. Though the replacement of its pyridine ring with a benzene ring maintained the mode of the H 2 -receptor blocking action of IT-066, the oxidation of the piperidine ring completely attenuated this blocking action. By replacing the connecting carbon chain of IT-066, cis -2-butene, with butane, trans -2-butene, or 2-butyne, the irreversible antagonism disappeared and the potency was reduced. On the other hand, BMY25368, whose connecting carbon chain is trimethylene, showed irreversible antagonism comparable to that of IT-066. Hydrolysis of the polar group of IT-066 completely attenuated the H 2 -receptor blocking activity. Among the compounds tested, only the compound that had 3,4-diamino-3-cyclobutene-1,2-dione as a polar group showed time-dependent and insurmountable H 2 -receptor blocking action. These data suggest the importance of the following structural features of IT-066: the piperidine ring of IT-066 and -NH 2 in its polar group are essential for the interaction with the H 2 -receptor; and the 3,4-diamino-3-cyclobutene-1,2-dione group and the connecting carbon chain of IT-066 are crucial for determining the irreversibility of H 2 -receptor blocking action, though the connecting carbon chain is replaceable with another chain with appropriate length and configuration.

Highly functionalized, unsymmetrical disulfides (presumed metabolites of a bioactive sulfide) were synthesized by a base-induced, crossed reaction of two different symmetrical disulfides. The reaction was also applied to the preparation of a vitamin B1 derivative, Prosultiamine.

Three compounds with a dihydrothiophene ring were synthesized as authentic samples to analyze human metabolites of Esonarimod, which has been developed as a new antirheumatic drug.

Sophoradin (I) [2′,4,4′-trihydroxy-3,3′,5-tris(3-methyl-2-butenyl)chalcone] which had been isolated from “Guang-Dou-Gen” (the root of Sophora subprostrata Chun et T. Chen) was synthesized through Claisen rearrangement. The reaction of p-hydroxybenzaldehyde and 3-chloro-3-methyl-1-butyne (III) gave 4-(1,1-dimethylpropargyloxy)benzaldehyde (VIII), which was catalytically hydrogenated over Lindlar catalyst to afford 4-(1,1-dimethylallyloxy)benzaldehyde (IX). IX was converted to 4-hydroxy-3-(3-methyl-2-butenyl)benzaldehyde (X) by Claisen rearrangement. The reaction of X and III gave 3-(3-methyl-2-butenyl)-4-(1,1-dimethylpropargyloxy)benzaldehyde (XI). Condensation of 2-hydroxy-4-(1,1-dimethylpropargyloxy)acetophenone (IV) and XI in alkaline solution gave a chalcone (XIII), which was catalytically hydrogenated over Lindlar catalyst to give 2′-hydroxy-4,4′-bis(1,-dimethylallyloxy)-3-(3-methyl-2-butenyl)chalcone (XIV). XIV was converted to I by Claisen rearrangement.

Sophoradin (I) [2′,4,4′-trihydroxy-3,3′,5-tris(3-methyl-2-buteny)chalcone] was synthesized through Claisen-Schmidt condensation followed by demethoxymethylation.Isoprenylation of p-hydroxybenzaldehyde with 3,3-dimethylallyl bromide in 10% potassium hydroxide solution gave 4-hydroxy-3,5-bis(3-methyl-2-butenyl)benzaldehyde (IX). Methoxymethylation of 2,4-dihydroxy-3-(3-methyl-2-butenyl)acetophenone (IV) and IX afforded 4-methoxymethoxy-IV (XVIII) and 4-methoxymethoxy-IX (XX). Condensation of XVIII and XX in 50% potassium hydroxide solution gave 2′-hydroxy-4,4′-bis(methoxymethoxy)-3,3′,5-tris(3-methyl-2-butenyl)chalcone (XXII). Hydrolysis of XXII with methanolic hydrochloric acid gave I which was identified with natural I by mixed mp, and IR and NMR spectra.

Two new flavanones, I and VII, and daidzein were isolated from Guang-Dou-Gen (the root of Sophora subprostrata CHUN et T.CHEN). Fom the spectral data and comparison with sophoranochromene and its derivative, the structure of I was established as 2-[{3'-hydroxy-2', 2'-dimethyl-8'-(3-methyl-2-butenyl)} chroman-6'-yl]-7-hydroxy-8-(3-methyl-2-butenyl) chroman-4-one. The structure of VII was formulated from the spectral data and biogenetic speculation as 2-[{2'-(1-hydroxy-1-methylethyl)-7'-(3-methyl-2-butenyl)-2'3'-dihydrobenzofuran}-5'-yl]-7-hydroxy-8-(3-mehtyl-2-butenyl) chroman-4-one.

Two new flavanones were isolated from Guang-Dou-Gen (the root of Sophora subprostrata CHUN et T.CHEN) and their structures were established from their spectral data and comparison with the corresponding synthesized derivatives as 4', 7-dihydroxy-6, 8-bis(3-methyl-2-butenyl)flavanone (I), and 2-[(7'-hydroxy-2', 2'-dimethyl-2H-benzopyran)-6'-yl]-7-hydroxy-8-(3-methyl-2-butenyl)chroman-4-one (XI).

Five dihydrochalcone derivatives, 2'-carboxymethoxy-4, 4'-bis (3-methyl-2-butenyloxy) dihydrochalcone (M-6-b), 2', 4-bis (carboxymethoxy)-4'-(3-methyl-2-butenyloxy) dihydrochalcone (M-2), 2', 4-bis (carboxymethoxy)-4'-(3-carboxy-2-butenyloxy) dihydrochalcone (M-1-a), 2', 4-bis (carboxymethoxy)-4'-(3-hydroxymethyl-2-butenyloxy) dihydrochalcone (M-1-b), and 2'-carboxymethoxy-4-hydroxy-4'-(3-methyl-2-butenyloxy) dihydrochalcone (M-4-b), which are the main metabolites in rats of a new anti-ulcer drug "sofalcone"(2'-carboxymethoxy-4, 4'-bis (3-methyl-2-butenyloxy) chalcone) were synthesized and the anti-ulcer activities of the major metabolites in humans, M-6-b, M-2, and M-1-a, were examined by Shay's and Takagi's methods and also by the use of rats with histamine-induced ulcer. The most active compound was M-6-b, which showed activity equal to or slightly weaker than that of sofalcone.

To investigate the anti-ulcer activity of the isoprenyl chalcone, sophoradin, which is present in a Chinese crude drug, Guang-dou-gen (the root of Sophora subprostrata), 30 related chalcones (1-30) were newly synthesized by condensation between substituted acetophenones and benzaldehydes, and their anti-ulcer activities were examined using Shay's pylorus-ligated rats, and water-immersed and restraint stress rats. Twenty-seven chalcones were substituted with isoprenyl or isoprenyloxyl groups and two with geranyloxyl groups (13, 30), with or without a carboxymethoxyl group, and one chalcone was substituted with allyloxyl group (14). All the chalcones were found to be effective by both methods. Several chalcones (2, 3, 8, 10, 11, 12, 15, 17, 22), each having more than one isoprenyloxyl group, exhibited high inhibitory ratios by both methods. In particular, 2', 4'-dihydroxy-3'-(3-methyl-2-butenyl)-4-(3-methyl-2-butenyloxy) chalcone (2), 2'-hydroxy-4, 4'-bis (3-methyl-2-butenyloxy) chalcone (10), and 2'-carboxymethoxy-4, 4'-bis (3-methyl-2-butenyloxy) chalcone (15) exhibited very high inhibitory ratios (70-100%) by both methods, and were as potent as sophoradin.

To investigate the anti-ulcer activity of the isoprenyl chalcone, sophoradin, which is present in a Chinese crude drug, Guang-dou-gen (the root of Sophora subprostrata), 30 related chalcones (1-30) were newly synthesized by condensation between substituted acetophenones and benzaldehydes, and their anti-ulcer activities were examined using Shay's pylorus-ligated rats, and water-immersed and restraint stress rats. Twenty-seven chalcones were substituted with isoprenyl or isoprenyloxyl groups and two with geranyloxyl groups (13, 30), with or without a carboxymethoxyl group, and one chalcone was substituted with allyloxyl group (14). All the chalcones were found to be effective by both methods. Several chalcones (2, 3, 8, 10, 11, 12, 15, 17, 22), each having more than one isoprenyloxyl group, exhibited high inhibitory ratios by both methods. In particular, 2', 4'-dihydroxy-3'-(3-methyl-2-butenyl)-4-(3-methyl-2-butenyloxy) chalcone (2), 2'-hydroxy-4, 4'-bis (3-methyl-2-butenyloxy) chalcone (10), and 2'-carboxymethoxy-4, 4'-bis (3-methyl-2-butenyloxy) chalcone (15) exhibited very high inhibitory ratios (70-100%) by both methods, and were as potent as sophoradin.

Five dihydrochalcone derivatives, 2'-carboxymethoxy-4, 4'-bis (3-methyl-2-butenyloxy) dihydrochalcone (M-6-b), 2', 4-bis (carboxymethoxy)-4'-(3-methyl-2-butenyloxy) dihydrochalcone (M-2), 2', 4-bis (carboxymethoxy)-4'-(3-carboxy-2-butenyloxy) dihydrochalcone (M-1-a), 2', 4-bis (carboxymethoxy)-4'-(3-hydroxymethyl-2-butenyloxy) dihydrochalcone (M-1-b), and 2'-carboxymethoxy-4-hydroxy-4'-(3-methyl-2-butenyloxy) dihydrochalcone (M-4-b), which are the main metabolites in rats of a new anti-ulcer drug "sofalcone"(2'-carboxymethoxy-4, 4'-bis (3-methyl-2-butenyloxy) chalcone) were synthesized and the anti-ulcer activities of the major metabolites in humans, M-6-b, M-2, and M-1-a, were examined by Shay's and Takagi's methods and also by the use of rats with histamine-induced ulcer. The most active compound was M-6-b, which showed activity equal to or slightly weaker than that of sofalcone.