Synthesis of methyl esters of 5-amino-4-(substituted amino)-2-methylthio-7H-pyrrolo[2,3d]-pyrimidine-6-carboxylic acids

The optimum route for the synthesis of methyl esters of N-[(4-substituted amino)-5-cyano-2-methylthiopyrimidin-6-yl]amino acids (which are starting materials for preparing the methyl esters of the corresponding 5-amino-4-(substituted amino)pyrrolo[2,3-d]pyrimidine-6-carboxylic acids) is via subsequent reactions of 4,6-dichloro-2-methylthiopyrimidine-5-carbonitrile with amines and methyl glycinate. In some examples, the reaction of methyl N-(4-chloro-2-methylthio-6-pyrimidinyl)aminoacetate with amines occurs to give the corresponding acid amides. The previously unknown synthesized derivatives of pyrimidin-6-yl amino acids and 4,5-diaminopyrrolo[2,3-d]pyrimidine- 6-carboxylic acids possess fungicidal properties.Vilnius University, Vilnius 2006, Lithuania. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No 7, pp. 955–961, July, 2000.     

The Synthesis of Novel Iodinated Iminodiacetic Acid Analogues as Hepatobiliary Imaging Agents

The synthesis and characterization of N-[2-[[4-iodo-2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N-(carboxymethyl)glycine and N-[2-[(4-iodo-2,6-diethylphenyl)amino]-2-oxoethyl]-N-(carboxymethyl)glycine is presented, as well as a modified and improved synthesis of N-[2-[(2,4-diiodo-6-methylphenyl)amino]-2-oxoethyl]-N-(carboxymethyl)glycine. These compounds are new agents for hepatobiliary imaging.     

The Synthesis of Novel Iodinated Iminodiacetic Acid Analogues as Hepatobiliary Imaging Agents

Summary. The synthesis and characterization of N-[2-[[4-iodo-2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N-(carboxymethyl)glycine and N-[2-[(4-iodo-2,6-diethylphenyl)amino]-2-oxoethyl]-N-(carboxymethyl)glycine is presented, as well as a modified and improved synthesis of N-[2-[(2,4-diiodo-6-methylphenyl)amino]-2-oxoethyl]-N-(carboxymethyl)glycine. These compounds are new agents for hepatobiliary imaging.     

Palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of organoboronic acids with N-protected 4-iodophenyl alanine linked isoxazoles

Suzuki-Miyaura coupling reaction of N-protected 4-iodopheyl alanine isoxazoles with arylboronic acids, catalyzed by palladium, efficiently produce benzyl-N-(4-bipheyl)-2-(3-methyl-5(E)-2-aryl-1-ethenyl-4- isoxazolyl)-amino-2-oxoethyl) carba-mates in good yields. This process is first of its kind to construct carbon-carbon bond formation having biaryl motif on amino acid linked isoxazole moiety.     

Novel synthesis of the pyrrolo[2,1-c][1,4]benzodiazocine ring system via a Dieckmann condensation

A novel four-step synthesis to the pyrrolo[2,1-c][1,4]benzodiazocine ring system is described. 1H-Pyrrole-2-carbaldehyde was alkylated with ethyl or methyl bromoacetate and the resulting ethyl or methyl (2-formyl-1H-pyrrol-1-yl)acetates oxidised with potassium permanganate to the corresponding 1-[(2-ethoxy or methoxy)-2-oxoethyl]-1H-pyrrole-2-carboxylic acids. The latter was converted into their acid chlorides by reaction with thionyl chloride and without isolation transformed into the respective methyl 2-({[1-(2-ethoxy or methoxy-2-oxoethyl)-1H-pyrrol-2-yl]carbonyl}amino)benzoates by reaction with methyl anthranilate. Dieckmann condensation of methyl 2-({[1-(2-methoxy-2-oxoethyl)-1H-pyrrol-2-yl]carbonyl}amino)benzoate provided the pyrrolo[2,1-c][1,4]benzodiazocine.     

Synthesis and Antinociceptive Activity of N -Substituted 4-Aryl-4-oxo-2-[(3-thiophen-2-yl)amino]but-2-enamides

2-{[5-Aryl-2-oxofuran-3(2H)-ylidene]amino}thiophene-3-carboxylic acid derivatives reacted with substituted amines to give new N-substituted 4-aryl-4-oxo-2-[(3-thiophen-2-yl)amino]but-2-enamides. Antinociceptive activity of the synthesized compounds was studied.     

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.     

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.     

Synthesis, photophysical, photochemical and biological properties of caged GABA, 4-[[(2H-1-benzopyran-2-one-7-amino-4-methoxy) carbonyl] amino] butanoic acid

The photorelease of a caged neurotransmitter can be used to investigate the function of neuronal circuits in tissues. We have designed and synthesized a stable, caged gamma-aminobutyric acid (GABA) derivative, 4-[[(2H-1-benzopyran-2-one-7-amino-4-methoxy)carbonyl]amino] butanoic acid (BC204), that releases the neurotransmitter in physiological medium when irradiated with UV light at 300-400 nm in PBS at pH 7.4. The release of GABA occurs with the formation of the major photoproduct, 7-amino-4-(hydroxymethyl)-2H-1-benzopyran-2-one, via a solvolytic photodegradation mechanism of the coumarin moiety and was confirmed by electrospray mass spectrometry/mass spectrometry (ESI MS/MS). BC204 is chemically stable and shows no intrinsic activity after many hours under physiological dark conditions. These properties suggest that BC204 is an excellent form of caged GABA that is well suited for long-term biological studies.     

2'-O-[2-(amino)-2-oxoethyl] oligonucleotides

[structure: see text] Oligonucleotides with novel modifications, 2'-O-[2-(amino)-2-oxoethyl] (2'-O-NAc), 2'-O-[2-(methylamino)-2-oxoethyl] (2'-O-NMAc), 2'-O-[2-(dimethylamino)-2-oxoethyl] (2'-O-DMAc), and 2'-O-[2-[[2-(dimethylamino)ethyl]amino]-2-oxoethyl] (2'-O-DMAEAc), have been synthesized. These modified oligonucleotides exhibit high binding affinity to complementary RNA (and not to DNA) and considerably enhance the nuclease stability of oligonucleotides with t(1/2) > 24 h.     

Synthesis of pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5-ones. Cyclization reaction of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid with acetic anhydride

Treatment of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid (X) with acetic anhydride under refluxing conditions afforded 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]-pyrimido[4,5-d]pyrimidin-5-one acetate (IX). The intermediate X was prepared from 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (V). The reaction of V with the sodium salt of 2-amino-3-hydroxypyridine at room temperature gave 4-(2-amino-3-pyridyloxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (VI). Treatment of VI with a hot aqueous sodium hydroxide solution and subsequent acidification gave X. Involvement of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecaroboxylic acid ethyl ester (VIII) (Smiles rearrangement product) as an intermediate in the above alkaline hydrolysis reaction of VI to X was demonstrated by the isolation of VIII and its subsequent conversion into X under alkaline hydrolysis conditions. Acetylation of VIII with acetic anhydride in pyridine solution gave 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester acetate (XI), which afforded IX on fusion at 220°. This alternative synthesis of IX from XI supported the structural assignment of IX. Fusion of VI gave 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]pyrimido]4,5-d]pyrimidin-5-one (VII). The latter was also obtained when VIII was fused at 210°. Acetylation of VII with acetic anhydride afforded IX.     

Synthesis and molecular structure of 3-(2-aryl-2-oxoethyl)-3-methoxy-2-oxo-2,3-dihydroimidazo-[1,2-<Emphasis Type="Italic">a</Emphasis>]pyridine hydrochlorides

Reactions between 2-pyridylamides of Z-4-aryl-2-hydroxy-4-oxobut-2-enoic acids with diazomethane have been used to synthesize 3-(2-aryl-2-oxoethyl)-3-methoxy-2-oxo-2,3-dihydroimidazo[1,2-a]pyridines, which form hydrochlorides with hydrochloric acid. The structure of the latter has been demonstrated by XRD for the hydrochloride of 3-methoxy-2-oxo-3-(2-phenyl-2-oxoethyl)-2,3-dihydroimidazo[1,2-a]pyridine. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 464–468, 2007.     

Synthesis of N-acyl-2-pyrrolidinones from the corresponding N-acyl-GABA derivatives

In this work, the synthesis of 1-(pyridine-3-carbonyl)pyrrolidin-2-one ( 1a ) and 1-(2-propyl-1-pentanoyl)pyrrolidin-2-one ( 1b ) by cyclization of the corresponding GABA derivatives, is reported. Two different methods are developed. For the synthesis of 1a , the parent molecule 4-[(pyridine-3-carbonyl)-amino]butanoic acid ( 2a ) is treated first with thionyl chloride and then with triethylamine. The second derivative, 1b , is produced by an intramolecular dehydration of 4-(2-propylpentanoylamino)butanoic acid ( 2b ) using an acid catalyst.     

The first synthesis of 3-nitro-4-[(s-tetrazin-3-yl)amino]furazans

Oxidation of 3-amino-4-[(s-tetrazin-3-yl)amino]furazans with peroxy acids or 30% H2O2/Na2WO4/H2SO4 system results in transformation of the amino group into the nitro one and is accompanied by formation of N-oxides at tetrazine moiety.     

Synthesis of substituted in benzene ring 4-[(2-aminophenyl)thio]-, 4-[(2-mercaptophenyl)amino]-2-methylquinolines and (4E)-4-[(2-mercaptophenyl)imino]-2-methyl-1,4-dihydroquinolines

By a reaction of 2-methyl-4-chloroquinolines with o-mercaptoaniline under various conditions synteses were performed of substituted in the benzene ring 4-[(2-aminophenyl)thio]-2-methylquinolines and (4E)-4-[(2-mercaptophenyl)imino]-2-methyl-1,4-dihydroquinolines that were respectively by isomerization or rearrangement converted into 4-[(2-mercaptophenyl)amino]-2-methylquinolines.     

2-氨基-3-氰基-4-芳基-6-二茂铁基吡啶的合成

以乙酰二茂铁、芳香醛、丙二腈为原料, 在乙酸铵存在下以乙醇为溶剂, 采用一锅煮的方法合成了8个2-氨基-3-氰基-4-芳基-6-二茂铁基吡啶化合物, 产率中等. 并通过X射线衍射分析确证产物4e的结构.     

A promising structural zinc enzyme model for CO2 fixation and calcification

A new ligand, namely, N-{tris([2-[(1-methylbenzimidazol-2-yl)ethyl]methyl]amino)-2-oxoethyl}iminodiacetic acid is synthesized and characterized and used to prepare a zinc complex as a promising model for the active site of the nacreous protein in mollusc shells. Preliminary investigation of CO₂ fixation and calcification is studied with regard to the influence of the pK_a value of the coordinated water molecule and the carboxylate groups.     

Reactions of 2-isocyanatobenzoyl chloride and 2-carbomethoxyphenyl isocyanate with 5-aminotetrazole

Treatment of 2-isocyanatobenzoyl chloride ( 4 ) with 5-aminotetrazole (5-AT) gave 3-(5-tetrazolyl)quinazoline-2,4(1H,3H)-dione ( 1 ) directly. Treatment of 2-carbomethoxyphenyl isocyanate ( 5 ) with 5-AT gave 2-[((5-amino-1H-tetrazol-1-yl)carbonyl)amino]benzoic acid methyl ester ( 6 ) as a kinetic product, which was thermally isomerized to 2-[((1H-tetrazol-5-ylamino)carbonyl)amino]benzoic acid methyl ester ( 7 ), the thermodynamically more stable urea. Cyclization of 7 with polyphosphoric acid gave 2-(1H-tetrazol-5-ylamino)-4H-3,1-benzoxazin-4-one ( 2 ). Urea 6 was quite labile in solution, as shown by nmr, and readily reacted with methanol to give 2-[(methoxycarbonyl)amino]benzoic acid methyl ester ( 10 ).     

Synthesis and antimicrobial activity of some derivatives of (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide

(7-Hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide (2) was prepared from (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid ethyl ester (1) and 100% hydrazine hydrate. Compound 2, is the key intermediate for the synthesis of several series of new compounds such as Schiff's bases 3a-l, formic acid N'-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)acetyl] hydrazide (4), acetic acid N'-[2-(7-hydroxy-2-oxo-2H-chromen-4- yl)-acetyl] hydrazide (5), (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid N'-[2-(4- hydroxy-2-oxo-2H-chromen-3-yl)-2-oxoethyl] hydrazide (6), 4-phenyl-1-(7-hydroxy-2- oxo-2H-chromen- 4-acetyl) thiosemicarbazide (7), ethyl 3-{2-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)-acetyl]hydrazono}butanoate (8), (7-hydroxy-2-oxo-2H-chromen-4-yl)- acetic acid N'-[(4-trifluoromethylphenylimino)methyl] hydrazide (9) and (7-hydroxy-2- oxo-2H-chromen-4-yl)acetic acid N'-[(2,3,4-trifluorophenylimino)-methyl] hydrazide (10). Cyclo- condensation of compound 2 with pentane-2,4-dione gave 4-[2-(3,5- dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-7-hydroxy-2H-chromen-2-one (11), while with carbon disulfide it afforded 7-hydroxy-4-[(5-mercapto-1,3,4-oxadiazol-2-yl)methyl]-2H- chromen-2-one (12) and with potassium isothiocyanate it gave 7-hydroxy-4-[(5- mercapto-4H-1,2,4-triazol-3-yl)methyl]-2H-chromen-2-one (14). Compound 7 was cyclized to afford 2-(7-hydroxy-2-oxo-2H-chromen-4-yl)-N -(4-oxo-2-phenylimino- thiazolidin-3-yl) acetamide (15).     

An improved synthesis of butyl 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetate (AU-224).

A new and facile route for the synthesis of the novel gastrointestinal prokinetic butyl 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetate (1b), which exhibited potent gastro- and colon-prokinetic activities by oral administration without significant side effects, was established. The key intermediate, butyl 4-amino-1-piperidineacetate (16), was prepared from commercially available 4-amino-1-benzylpiperidine (2) in a high yield with four steps. Compound 1b was prepared by condensation of commercially available 4-amino-5-choloro-2-methoxybenzoic acid (7) with 16 in 84% yield. This improved synthetic route was appropriate for large-scale synthesis of 1b.