Studies on proton pump inhibitors. II. Synthesis and antiulcer activity of 8-[(2-benzimidazolyl)sulfinylmethyl]-1,2,3,4-tetrahydroquinolines and related compounds

Many 8-[(2-benzimidazolyl)sulfinylmethyl]-1,2,3,4-tetrahydroquinolin e derivatives were synthesized and tested for their (H+ + K+)adenosine triphosphatase (ATPase)-inhibitory and antisecretory activities against histamine-induced gastric acid secretion in rats. These sulfinyl compounds were synthesized by the oxidation of the corresponding sulfides, which were obtained from the reaction of 8-chloromethyl-1,2,3,4-tetrahydroquinolines and 2-mercaptobenzimidazoles in the presence of potassium carbonate. All compounds tested were potent inhibitors of (H+ + K+)ATPase. Most of the compounds showed antisecretory activity. Among them, 8-[(2-benzimidazolyl)sulfinylmethyl]-1-ethyl-1,2,3,4-tetrahydro quinoline (IXa) was found to have the most potent activity. The structure-activity relationships are discussed.     

Synthesis and antiulcer activity of 4-substituted 8-[(2-benzimidazolyl)sulfinylmethyl]-1,2,3,4-tetrahydroquinoli nes and related compounds

A series of 4-substituted 8-[(2-benzimidazolyl)sulfinylmethyl]-1,2,3,4-tetrahydroquinolin es was synthesized and examined for their (H+ + K+)adenosine triphosphatase (ATPase)-inhibitory and antisecretory activities against histamine-induced gastric acid secretion in rats. Many compounds tested were potent inhibitors of (H+ + K+)ATPase. Most compounds showed antisecretory activity. The antiulcer activity against water-immersion stress-induced gastric ulcer, aspirin-induced gastric ulcer and gastric necrosis induced by hydrochloric acid also were tested in the rat. Some of these compounds, in particular, 4-(N-allyl-N-methylamino)-1-ethyl-8-[(5-fluoro-6-methoxy-2-benzimidazoly l) sulfinylmethyl]-1-ethyl-1,2,3,4-tetrahydroquinoline (XVIIx) were found to have potent activity. The structure-activity relationships are discussed.     

Synthesis of 3-[[(2-benzimidazolyl)thio]methyl]-1-methyl-1,8-dihydrocycloheptapyrazol-8-ones

3-(Bromoacetyl)tropolone was reacted with five 2-mercaptobenzimidazoles to give 3-[[(2-benzimidazolyl)thio]acetyl]tropolones. These products were heated with methylhydrazine to afford 3-[[(2-benzimidazolyl)thio]methyl]-1-methyl-1,8-dihydrocycloheptapyrazol-8-ones. In these reactions, 1-methyl-3-[(1-methylhydrazino)methyl]-1,8-dihydrocycloheptapyrazol-8-one was isolated as a minor product.     

Retinoidal pyrimidinecarboxylic acids. Unexpected diaza-substituent effects in retinobenzoic acids

Several pyridine- and pyrimidine-carboxylic acids were synthesized as ligand candidates for retinoid nuclear receptors, retinoic acid receptors (RARs) and retinoic X receptors (RXRs). Although the pyridine derivatives, 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]pyri dine-3-carboxylic acid (2b) and 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]py ridine-3-carboxylic acid (5b) are more potent than the corresponding benzoic acid-type retinoids, Am80 (2a) and Am580 (5a), the replacement of the benzene ring of Am580 (5a), Am555 (6a), or Am55 (7a) with a pyrimidine ring caused loss of the retinoidal activity both in HL-60 cell differentiation assay and in RAR transactivation assay using COS-1 cells. On the other hand, pyrimidine analogs (PA series, 10 and 11) of potent RXR agonists (retinoid synergists) with a diphenylamine skeleton (DA series, 8 and 9) exhibited potent retinoid synergistic activity in HL-60 cell differentiation assay and activated RXRs. Among the synthesized compounds, 2-[N-n-propyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)a mino]pyrimidine-5-carboxylic acid (PA013, 10e) is most active retinoid synergist in HL-60 assay.     

Synthesis and antimalarial effects of 5,6-dichloro-2-[(4-||4-(diethylamino)-i-methylbutyl] amino||-6-methyl-2-pyrirnidinyl)amino] benzimidazole and related benzimidazoles and lH-imidazo[4,5-b] pyridines

A group of fifty-five 2-[(4-11[(dialkylamino)alkyI]amino11-6-methyl-2-pyrimidinyl)amino]-benzimidazoles (VII) was synthesized in 3-88% yield by the condensation of the requisite 2-[(2-benzimidazolyl)amino]-4-chloro-6-methylpyrimidine (VI) with the appropriate polyamine in ethanol-hydrochloric acid or neat with excess amine containing potassium iodide. The 2-[(2-benzimidazolyl)amino]-6-methyl-4-pyrirnidinol precursors (V), obtained in 11-51% yield by cyclization of 2-(cyanoamino)-4-hydroxy-6-methylpyrimidine with a suitably substituted o-phenylenediamine, were chlorinated with phosphorus oxychloride to give the intermediate 2-[(2-benzimidazolyl)amino]-4-chloro-6-rnethylpyrimidines (VI) (27-99%). Oxidation of 5,6-dichloro-2-[(4-11[4-(diethylamino)-l-methylbutyl] amino 11-6-methyl-2-pyrimidinyl) amino ]benzimidazole ( 29 ) with m-chloroperbenzoic acid gave the distal N⁴'-oxide ( 31 ) (19%). Fusion of 2,3-uiaminopyridine with 2-(cyanoamino)-4-hydroxy-6-methylpyrimidine provided 2-[(4-hydroxy-6-tnethyl-2-pyrimidinyl)amino]-lH-imitlazo[4,5-b]pyrimidine (VIII) (30%), which upon chlori-nation with phosphorus oxychloride (63%) followed by amination with i N, N-diethylethylene-diamine afforded 2-(4-11[2-(diethylamino)ethyl] amino 11-6-methyl-2-pyrimidinyl)-lH-imidazo [4,5-b]pyridine (X) (8%). Thirty-eight of the novel 2-[(4-amino-6-methyl-2-pyrimidinyl)amino]-benzimidazoles possessed “curative” activity against Plasmodium berghei at single subcutaneous doses ranging from 20.640 mg./kg. Orally, thirty-one compounds exhibited suppressive activity against P. berghei comparable with or superior to the reference drugs 1-(p-chlorophenyl)-3-(4-11[2-(diethylarnino)ethyl]amino 11-6-methyl-2-pyrimidinyl)guanidine (I) and quinine hydrochloride, while twelve of them were 5 to 28 times as potent as I and quinine hydrochloride. Eight compounds also displayed strong suppressive activity against P. gallinaceum in chicks. 5,6-Dichloro-2-[(4-112-(diethylamino)ethyl]amino11-6-methyl-2-pyrimidinyl] benzimidazole (18) showed marked activity against a cycloguanil-resistant line of P. berghei, and the most promising member of the series, namely 5,6-dichloro-2-[(4-11[4-(diethylamino)-l-methylbutyl]amino11-6-methyl-2-pyrimidinyl)amino]benzimidazole ( 29 ) (Q = 28), was designated for preclinical toxico-logical studies and clinical trial. Structure-activity relationships are discussed.     

Remote asymmetric trifluoromethylation induced by chiral sulfinyl group: synthesis of enantiomerically pure 1-(2-naphthyl)-2,2,2-trifluoroethanol

The reaction of 1-[(2,4,6-triisopropylphenyl)sulfinyl]-2-naphthaldehyde with (trifluoromethyl)trimethylsilane using tetramethylammonium fluoride gave trifluoromethylated compounds in high yield with high diastereoselectivity. Desilylation and subsequent recrystallization yielded the enantiomerically and diastereomerically pure trifluoroethanol, which afforded chiral 1-(2-naphthyl)-2,2,2-trifluoroethanol after removal of the sulfinyl group.     

Saturated heterocycles. 242. Synthesis of 2-substituted-6-(6′,7′-dimethoxy-3′,4′-dihydro-1′-isoquinolyl)-5,6,7,8-tetrahydro- quinazolin-4(3H)-one Derivatives

In the reactions of the recently synthesized β-ketoesters 1-[(3′-methoxycarbonyl- and 1-[(3′-ethoxycarbonyl-4′-oxo)-1′-cyclohexyl]-3,4-dihydroisoquinoline 4, 5 with amidines or cyclic guanidines, a number of 2-substituted-6-(6′,7′-dimethoxy-3′,4′-dihydro-1′-isoquinolyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one derivatives 6–8 were prepared. The new compounds possess various pharmacological actions.     

Tetra-2,3-pyrazinoporphyrazines with externally appended pyridine rings. 3. A new highly electron-deficient octacationic macrocycle: tetrakis-2,3-[5,6-di{2-(N-methyl)pyridiniumyl}pyrazino]porphyrazine, [(2-Mepy)8TPyzPzH(2)]8+

A new octacationic macrocycle, tetrakis-2,3-[5,6-di{2-(N-methyl)pyridiniumyl}pyrazino]porphyrazine, was obtained in its hydrated form as the water-soluble iodide salt. This compound, abbreviated as [(2-Mepy)(8)TPyzPzH(2)](I(8)).8H(2)O (2-Mepy = 2(N-methyl)pyridiniumyl moiety), was obtained by demetalation of the corresponding Mg(II) complex, [(2-Mepy)(8)TPyzPzMg(H(2)O)](I(8)).5H(2)O, which in turn was prepared from its corresponding neutral hydrated species tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazinato(monoaquo)magnesium(II), [Py(8)TPyzPzMg(H(2)O)].4H(2)O, by reaction with CH(3)I in N,N-dimethylformamide. The quaternization reactions by using CH(3)I or methyl p-toluenesulfonate were also conducted on the monomeric precursor 2,3-dicyano-5,6-di(2-pyridyl)-1,4-pyrazine, [(CN)(2)Py(2)Pyz], with formation of the monoquaternized ion [(CN)(2)Py(2-Mepy)Pyz](+) neutralized by iodide and p-toluenesulfonate anions. Single-crystal X-ray work allowed elucidation of the structure of the two salt-like species. The diquaternized ion [(CN)(2)(2-Mepy)(2)Pyz](2+) could also be obtained as a p-toluenesulfonate salt, but attempts at direct macrocyclization of this dicationic species were unsuccessful. The iodide salt [(2-Mepy)(8)TPyzPzH(2)](I(8)).8H(2)O is water-soluble, with different solubilities depending on the range of pH explored. It was established that the macrocycle [(2-Mepy)(8)TPyzPzH(2)](8+) undergoes facile deprotonation and behaves as a strong acid. Aggregation phenomena are observed for both the octacation [(2-Mepy)(8)TPyzPzH(2)](8+) and its corresponding centrally deprotonated species [(2-Mepy)(8)TPyzPz](6+). Nevertheless, both cationic moieties exist in their monomeric form under specific experimental conditions. UV-visible monitored titrations with NaOH provide information about the type of protonation/deprotonation equilibria which are complicated by the occurrence of aggregation phenomena.     

Reaction of 4-Substituted 1-[(Difluoromethyl)sulfinyl]-2,3,4,5-tetrafluorobenzenes with Ammonia and Methylamine

Russian Journal of Organic Chemistry - The reaction of 4-X-substituted 1-[(difluoromethyl)sulfinyl]-2,3,5,6-tetrafluorobenzenes (X = CF3, H, OMe) with methylamine and ammonia in MeCN, Et2O, and...     

Synthesis, structure, and magnetic properties of valence ambiguous dinuclear antiferromagnetically coupled cobalt and ferromagnetically coupled iron complexes containing the chloranilate(2-) and the significantly stronger coupling chloranilate(*3-) radical trianion

Dinuclear [(TPyA)MII(CA2-)MII(TPyA)]2+ [TPyA=tris(2-pyridylmethyl)amine; CA2-=chloranilate dianion; M=Co (1(2+)), Fe (2(2+))] complexes have been prepared by the reaction of M(BF4)(2).6H2O, TPyA, H2CA, and triethylamine in MeOH solution. Their reduced forms [(TPyA)MII(CA*3-)MII(TPyA)]+ [M=Co(1+), Fe (2+)] have been synthesized by using cobaltocene, and oxidized forms of 1, [(TPyA)CoIII(CAn)CoIII(TPyA)]z+ [z=3, n=3- (1(3+)); z=4, n=2- (1(4+))], have been obtained by using FcBF4 and ThianBF4 (Fc=ferrocenium; Thian=thianthrinium), respectively. The dinuclear compound bridged chloranilates (CA2- or CA*3-) were isolated and characterized by X-ray crystallography, electrochemistry, magnetism, and EPR spectroscopy. Unlike the other redox products, valence ambiguous 13+ forms via a complex redox-induced valence electron rearrangement whereby the one-electron oxidation of the [CoIICA2-CoII]2+ core forms [CoIIICA*3-CoIII]3+, not the expected simple 1-e- transfer mixed-valent [CoIICA2-CoIII]3+ core. The M ions in 1 and 2 have a distorted octahedral geometry by coordination with four nitrogens of a TPyA, two oxygens of a chloranilate. Due to the interdimer offset face-to-face pi-pi and/or herringbone interactions, all complexes show extended 1-D and/or 2-D supramolecular structures. The existence of CA*3- in 1(3+) is confirmed from both solid-state magnetic and solution EPR data. Co-based 1n+ exhibit antiferromagnetic interactions [1(2+): g=2.24, J/kB=-0.65 K (-0.45 cm-1); 1+: g=2.36, J/kB=-75 K (52 cm-1)], while Fe-based 2n+ exhibit ferromagnetic interactions [2(2+): g=2.08, J/kB=1.0 K (0.70 cm-1); 2+: g=2.03, J/kB=28 K (19 cm-1)] [H=-2JS1.S2 for 12+ and 2(2+); H=-2J(S1.S2+S2.S3) for 1+ and 2+]. Thus, due to direct spin exchange CA*3- is a much strong spin coupling linkage than the superexchange spin-coupling pathway provided by CA2-.     

Synthesis and structure-activity relationships of substituted 2-[(2-imidazolylsulfinyl)methyl]anilines as a new class of gastric H+/K(+)-ATPase inhibitors. II.

A series of 2-[(2-imidazolylsulfinyl)methyl]anilines (2) having various substituents on their imidazole and aniline rings was synthesized and examined for their H+/K(+)-ATPase (adenosine triphosphatase) inhibitory effects and antisecretory activity against histamine-stimulated gastric acid secretions in Heidenhain pouch dogs. Although substitutions on the imidazole ring did not enhance biological activity, substitutions on the aniline ring by electron-donating substituents potently enhanced the enzyme inhibitory activity and also showed an inhibitory effect on histamine-stimulated gastric acid secretion after oral administration. In particular, the in vitro activity of the dimethyl (2u--w) and trimethyl (2ac) derivatives was about 10 times that of omeprazole. Also, 4-methyl (2k), 4-methoxy-5-methyl (2y) and 3,5-dimethyl-4-methoxy (2ab) derivatives showed a potent antisecretory effect of more than 80% after oral administration at 6 mg/kg. Although these aniline derivatives have relatively low stabilities in aqueous solution, replacement of the isobutyl group at the aniline nitrogen atom with N-(2-methoxyethyl) group enhanced the stability.     

Triangular oxalate clusters [W(3)(mu(3)-S)(mu(2)-S(2))(3)(C(2)O(4))(3)](2)(-) as building blocks for coordination polymers and nanosized complexes

The reaction of aqueous [W3S7(C2O4)3](2-) with Ln(3+) and Th(4+) in a 1:1 molar ratio leads to oxalate-bridged heteropolynuclear molecular complexes and coordination polymers. La(3+) and Ce(3+) give a layered structure with big (about 1.8 nm) honeycomb pores which are filled with water molecules and lanthanide ions, in {[Ln(H2O)6]3[W3S7(C2O4)3]4}Br x xH2O (Ia and Ib). The smaller Pr(3+), Nd(3+), Sm(3+), Eu(3+), and Gd(3+) ions give discrete nanomolecules [(W3S7(C2O4)3Ln(H2O)5)2(mu-C2O4)] (with a separation of about 3.2 nm between the most distant parts of the molecule), which are further united into zigzag chains by specific S2...Br- contacts to achieve the overall stoichiometry K[(W3S7(C2O4)3Ln(H2O)5)2(mu-C2O4)]Br.xH2O (IIa-IId). Th(4+) gives K2[(W3S7(C2O4)3)4Th2(OH)2(H2O)10] x 14.33H2O (III) with a nanosized discrete anion (with a separation of about 2.7 nm between the most distant parts of the molecule), in which two thorium atoms are bound via two hydroxide groups into the Th2(OH)2(6+) unit, and each Th is further coordinated by five water molecules and two monodentate [W3S7(C2O4)](2-) cluster ligands. All compounds were characterized by X-ray structure analysis and IR spectroscopy. Magnetic susceptibility measurements in the temperature range of 2-300 K show weak antiferromagnetic interactions between two lanthanides atoms for compounds IIa, IIb, and IId. The thermal decomposition of Ia, Ib, and IIb was studied by thermogravimetry.     

Antiangiogenic polyketides from Peperomia dindygulensis Miq

Two new polyketides: 2Z-(heptadec-12-enyl)-4-hydroxy-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one (1) and 2-(heptadec-12-enyl)-5-hydroxy-5,6,7,8-tetrahydrochromen- 4-one (2), together with eleven known compounds: 4-hydroxy-2-[(3,4-methylenedioxy- phenyl)tridecanoyl] cyclohexane-1,3-dione (3), oleiferinone (4), 4-hydroxy-2-[(3,4- methylenedioxyphenyl)undecanoyl]cyclohexane-1,3-dione (5), 4-hydroxy-2-[(11-phenyl- undecanoyl)cyclohexane-1,3-dione (6), proctorione C (7), surinone C (8), 5-hydroxy- 7,8,4'-trimethoxyflavone (9), 5-hydroxy-7,8,3',4'-tetramethoxyflavone (10), 5-hydroxy- 7,3',4'-trimethoxyflavone (11), 5,8-dihydroxy-7,3',4'-trimethoxyflavone (12) and cepharanone B (13) were isolated from the whole plant of Peperomia dindygulensis Miq. Their structures were elucidated by spectroscopic methods, including 2D-NMR techniques. Compounds 2, 3, 5 and 8 inhibited human umbilical vein endothelial cell (HUVEC) proliferation and compounds 5 and 8 sharply suppressed HUVEC tube formation.     

Aminoacid N-substituted 1,4,7-triazacyclononane and 1,4,7,10-tetraazacyclododecane Zn2+, Cd2+ and Cu2+ complexes. A preparative, potentiometric titration and NMR spectroscopic study

The pK(a)s and Zn2+, Cd2+ and Cu2+ complexation constants (K) for 1,4,7-tris[(2'S)-acetamido-2'-(methyl-3'-phenylpropionate)]-1,4,7-triazacyclononane, 1, 1,4,7-tris[(2'S)-acetamido-2'-(1'-carboxy-3'-phenylpropane)]-1,4,7-triazacyclononane, H(3)2, 1,4,7-tris[(2'S)-acetamido-2'-(methyl-3'-(1H-3-indolyl)propionate)]-1,4,7-triazacyclononane, 3, and 1,4,7,10-tetrakis[(2'S)-acetamido-2'-(methyl-3'-phenylpropionate)]-1,4,7,10-tetraazacyclododecane, 4, 1,4,7,10-tetrakis[(2'S)-acetamido-2'-(1'-carboxy-3'-phenylpropane)]-1,4,7,10-tetraazacyclododecane, H(4)5, in 20 : 80 v/v water-methanol solution are reported. The pK(a)s within the potentiometric detection range for H(3)1(3+) = 8.69 and 3.59, for H(6)2(3+) = 9.06, 6.13, 4.93 and 4.52, H(3)3(3+) = 8.79 and 3.67, H(4)4(4+) = 8.50, 5.62 and 3.77 and for H(8)5(4+) = 9.89, 7.06, 5.53, 5.46, 4.44 and 4.26 where each tertiary amine nitrogen is protonated. The complexes of 1: [Zn(1)]2+(9.00), [Cd(1)]2+ (6.49), [Cd(H1)]3+ (4.54) and [Cu(1)]2+ (10.01) are characterized by the log(K/dm3 mol(-1)) values shown in parentheses. Analogous complexes are formed by 3 and 4: [Zn(3)]2+ (10.19), [Cd(3)]2+ (8.54), [Cu(3)]2+ (10.77), [Zn(4)]2+ (11.41) [Cd(4)]2+ (9.16), [Cd(H4)]3+ (6.16) and [Cu(4)]2+ (11.71). The tricarboxylic acid H(3)2 generates a greater variety of complexes as exemplified by: [Zn(2)-] (10.68) [Zn(H2)] (6.60) [Zn(H(2)2)+] (5.15), [Cd(2)](-) (4.99), [Cd(H2)] (4.64), [Cd(H2(2))]+ (3.99), [Cd(H(3)2)]2+ (3.55), [Cu(2)](-) (12.55) [Cu(H2)] (7.66), [Cu(H(2)2)]+ (5.54) and [Cu(2)2](4-) (3.23). The complexes of H(4)5 were insufficiently soluble to study in this way. The 1H and 13C NMR spectra of the ligands are consistent with formation of a predominant Zn2+ and Cd2+ Delta or Lambda diastereomer. The preparations of the new pendant arm macrocycles H(3)2, 3, 4 and H(4)5 are reported.     

2,5-Dioxido-1,4-benzoquinonediimine (H2L2-), a hydrogen-bonding noninnocent bridging ligand related to aminated topaquinone: different oxidation state distributions in complexes [{(bpy)2Ru}2(mu-H2L)]n (n=0,+,2+,3+,4+) and [{(acac)2Ru}2(mu-H2L)]m (m=2-,-,0,+,2+)

The symmetrically dinuclear title compounds were isolated as diamagnetic [(bpy)2Ru(mu-H2L)Ru(bpy)2](ClO4)2 (1-(ClO4)2) and as paramagnetic [(acac)2Ru(mu-H2L)Ru(acac)2] (2) complexes (bpy=2,2'-bipyridine; acac- = acetylacetonate = 2,4-pentanedionato; H2L = 2,5-dioxido-1,4-benzoquinonediimine). The crystal structure of 22 H2O reveals an intricate hydrogen-bonding network: Two symmetry-related molecules 2 are closely connected through two NH(H2L2-)O(acac-) interactions, while the oxygen atoms of H2L2- of two such pairs are bridged by an (H2O)8 cluster at half-occupancy. The cluster consists of cyclic (H2O)6 arrangements with the remaining two exo-H2O molecules connecting two opposite sides of the cyclo-(H2O)6 cluster, and oxido oxygen atoms forming hydrogen bonds with the molecules of 2. Weak antiferromagnetic coupling of the two ruthenium(III) centers in 2 was established by using SQUID magnetometry and EPR spectroscopy. Geometry optimization by means of DFT calculations was carried out for 1(2+) and 2 in their singlet and triplet ground states, respectively. The nature of low-energy electronic transitions was explored by using time-dependent DFT methods. Five redox states were reversibly accessible for each of the complexes; all odd-electron intermediates exhibit comproportionation constants K(c)>10(8). UV-visible-NIR spectroelectrochemistry and EPR spectroscopy of the electrogenerated paramagnetic intermediates were used to ascertain the oxidation-state distribution. In general, the complexes 1n+ prefer the ruthenium(II) configuration with electron transfer occurring largely at the bridging ligand (mu-H2Ln-), as evident from radical-type EPR spectra for 13+ and (+. Higher metal oxidation states (iii, iv) appear to be favored by the complexes 2m; intense long-wavelength absorption bands and RuIII-type EPR signals suggest mixed-valent dimetal configurations of the paramagnetic intermediates 2+ and 2-.     

Studies on antiulcer drugs. III. Synthesis and antiulcer activities of imidazo[1,2-a]pyridinylethylbenzoxazoles and related compounds. A novel class of histamine H2-receptor antagonists.

A series of imidazo[1,2-a]pyridinylalkylbenzoxazole derivatives was synthesized and tested for histamine H2-receptor antagonist, gastric antisecretory and antiulcer activities. Some of 2-amino-6-[2-(imidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole derivatives were found to have good pharmacological activities. Among them, 2-amino-6-[2-(7-methoxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl] benzoxazole (II-11) and 2-acetamido-6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl] benzoxazole (II-38) showed potent antisecretory and cytoprotective activity. The structure-activity relationships of these compounds are discussed.     

Synthesis and pharmacological evaluation of 2-(1-alkylpiperidin-4-yl)-n-[(1r)-1-(4-fluorophenyl)-2-methylpropyl]acetamide Derivatives as Novel Antihypertensive Agents

We synthesized and evaluated the inhibitory activity of a series of 2-(1-alkylpiperidin-4-yl)-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]acetamide derivatives against T-type Ca(2+) channels. Structure-activity relationship studies revealed that the position of the amide structure was important for the potent inhibitory activity toward T-type Ca(2+) channels. In addition, the introduction of an appropriate substituent on the pendant benzene ring played a crucial role for the selectivity towards T-type Ca(2+) channels over L-type Ca(2+) channels and the potent bradycardic activity of these derivatives. Oral administration of N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-2-(1-{2-[2-(2-methoxyethoxy)phenyl]ethyl}piperidin-4-yl)acetamide (4f), which had superior selectivity for T-type Ca(2+) channels over L-type Ca(2+) channels, lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, which is often caused by traditional L-type Ca(2+) channel blockers.     

Studies on antiulcer drugs. I. Synthesis and antiulcer activities of imidazo[1,2-alpha]pyridinyl-2-oxobenzoxazolidines-3-oxo-2H-1,4-benzoxaz ines and related compounds.

A series of imidazo[1,2-alpha]pyridinyl-2-oxobenzoxazolidines (4a-i), -3-oxo-2H-1,4-benzoxazines (5a-q), their thio-analogues (4j-p and 5r-t) and 5,6,7,8-tetrahydroimidazo[1,2-alpha]pyridinyl derivatives (8 and 9) were synthesized and tested for anti-stress ulcer activity in rats. Several compounds were found to be more active than the reference compounds, zolimidine, cimetidine and sucralfate. Among them, compound 4e, 5i and 5l also exhibited potent protective activity against ethanol-induced gastric lesion. The synthesis and structure-activity relationships of these compounds are discussed.     

Synthesis of 2-[[(4-fluoroalkoxy-2-pyridyl)methyl]sulfinyl]-1H- benzimidazoles as antiulcer agents

Many 2-[[(4-fluoroalkoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazoles were synthesized and tested for anti-secretory, antiulcer, and cytoprotective activities. Most of these compounds were superior to omeprazole in anti-secretory and antiulcer potencies, and especially in protecting the gastric mucosa from ethanol-induced damage. Among these compounds, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl] - 1H-benzimidazole, AG-1749 (lansoprazole) (6f), was selected for further development and clinical evaluation.     

Orally active GPIIb/IIIa antagonists: synthesis and biological activities of masked amidines as prodrugs of 2-[(3S)-4

To improve the in vivo potency of the potent GPIIb/IIIa antagonist 2-[(3S)-4-[(2S)-2-(4-amidinobenzoylamino)-3-(4-methoxyphenyl)propanoyl]-3-(2-methoxy-2-oxoethyl)-2-oxopiperazinyljacetic acid (4), the amidino group was converted to an oxadiazole ring, thiadiazole ring or substituted amidoxime group. These groups were expected to be metabolized to an amidino group in vivo. The compounds synthesized were evaluated for their potency to inhibit the ex vivo adenosine 5'-diphosphate (ADP)-induced aggregation of guinea pig platelets. Among the compounds examined, the methoxycarbonyloxyamidine 8a exhibited the most potent ex vivo inhibitory activity with a fast onset and prolonged duration of action after oral administration.