Cyclopentyl derivatives of 8-azahypoxanthine and 8-azaadenine. Carbocyclic analogs of 8-azainosine and 8-azaadenosine

Four types of carboeyclic analogs of 8-azahypoxanthine and 8-azaadenine nucleosides have been prepared. This group of analogs is comprised of derivatives having the (±)-as-3-(hydroxy-methyl)cyclopentyl,(±)-trans-3-hydroxy-cis-4-(hydroxymethyl)cyclopentyl), (±)-trans-2-hydroxy-cis-4-(hydroxymethyl)cyclopentyl, and (±)-trans-2, trans-3-dihydroxy-cis-4-(hydroxymethyl)-cyelopentyl groups at position 3 of 3,6-dihydro-7H-v-triazolo[4,5-d]pyrimidm-7-one and of 7-amino-3H-v-triazolo[4,5-d]pyrimidine. Diazotization of (5-amino-6-chloropyrimidin-4-yl-amino)eyclopentane derivatives and acidic hydrolysis, without isolation of the resulting 7-chloro-3H-v-triazolo[4,5-d]pyrimidines yielded the 8-azahypoxanthine derivatives (III). Treatment of unpurified 7-chloro-3H-v-triazolo[4,5-d]pyrimidines with anhydrous ammonia gave the 8-azaadenine derivatives (IV). The cyclopentane analogs of 8-azaadenylic acid and of 8-aza-adenosine 3′,5′ -cyclic monophosphate were prepared from the 8-azaadenosine analog.     

Synthesis and biological evaluation of nucleosides containing 8-amino-imidazo[1,2-α]pyrazine as an isosteric replacement for adenine

A number of novel C-nucleosides related to purine derivatives are described in which the purine moiety has been replaced by the isosteric heterocycle, 8-aminoimidazo[1,2-α]pyrazine. The nucleosides prepared include the ribo, 3′-deoxy, 2′,3′-dideoxy, and 2′,3′-unsaturated derivatives. These C-nucleosides represent derivatives containing acid stable glycosyl bonds and they can be considered as analogs of adenine- or 3-deazaade-nine-containing nucleosides. Preparation of the parent ribonucleoside was accomplished by reaction of the C-l functionalized sugar, (2ξ)-1-amino-3,6-anhydro-l-deoxy-4,5-O-isopropylidene-7-O-trityl-D-allo-heptitol with 2,3-dichloropyrazine, followed by ring closure to the 8-chloroimidazo[1,2-α]pyrazine nucleoside, conversion to the 8-amino derivative and deblocking. A single crystal X-ray structure of the parent 8-amino-3-(β-D-ribofuranosyl)imidazo[1,2-α]pyrazine is described and the conformation compared to that of formycin. The sugar-modified analogs were prepared by subsequent functional group manipulations on the sugar moiety. Biological evaluation against HIV in H9 T-lymphoid cell culture showed the nucleosides to be devoid of significant antiviral activity compared to DDA. The 3-deazaadenosine analog also demonstrated weak suppression of mouse splenic NK activity toward YAC cells (mouse lymphoma cell targets). The imidazo[1,2-α]pyrazine analog of 3-deazaadenosine showed antiinflammatory activity in vivo in the rat pleurisy carrageenan model in the same range with 3-deazaadenosine.     

Saturated heterocycles. 254 . synthesis and stereochemistry of saturated or partially saturated pyridazino-[6,1-b]- and phthalazino[1,2-b]quinazolinones

By the reaction of anthranilic hydrazide 1 with cis-2-(p-methylbenzoyl)-1-cyclohexanecarboxylic acid 2a or diendo-3-(p-methylbenzoyl)bicyclo[2.2.1]heptane-2-carboxylic acid 2b , fused tetra- and pentacyclic ring systems 3a, b were prepared, trans-2-Amino-1-cyclohexanecar-bohydrazide 4b was reacted with 3-(p-chlorobenzoyl)propionic acid 5 to yield the pyridazino[6,1-b]quinazolinone 6 . From the reaction of cis-2-amino-1-cyclohexanecarbohydrazide 4a with 2a , three isomeric partially saturated 8H-phthalazino[1,2-b]quinazolin-8-ones 7a-c were formed. The reaction of diexo-2-aminobicyclo[2.2.1]heptane-3-carbohydrazide 4c and 2a furnished the pentacyclic derivatives 8 and 9 containing a 3-aryl-4,5-dihydropyridazine or 3-arylhexahydropyridazine ring C with cis annelated C/D rings. The formation of 8 and 9 involving different ring systems can be rationalized by two reaction pathways: (i) in the bislactam 9 the carboxyl group acylates the hydrazide, while (ii) in 8 it forms a pyridazine ring with the cyclic amino group by cyclocondensation. The structures of the products were elucidated by ¹H and ¹³C nmr methods, including DEPT, DNOE and 2D-HSC measurements.     

Synthesis of the carbocyclic analogs of uracil nucleosides

Treatment of the required hydroxyl derivatives of cis-3-aminocyclopentanemethanol with 3-ethoxyacryloyl isocyanate gave N-(3-ethoxyacryloyl)-N′-[hydroxy- or dihydroxy(hydroxy-methyl)cyclopentyl]ureas. Cyclization of the ureas in dilute sulfuric acid afforded high yields of the carbocyclic analogs of uridine, 2′-deoxyuridine, and 3′-deoxyuridine. The uridine and 3′-deoxyuridine analogs were also obtained in good yields by cyclizing the ureas in concentrated aqueous ammonia. None of the three analogs showed activity in tests versus KB cells in culture or L1210 leukemia in vivo.     

Synthesis of certain N- and C-alkyl purine analogs

A number of N- and C-alkyl derivatives of selected guanine analogs have been synthesized as potential antiviral agents. n-Pentyl, n-hexyl and 6-hydroxyhexyl derivatives in the imidazo[1,2-α]-s-triazine, 9–11 , imid-azo[1,2-α]pyrimidine, 13–17 , and thiazolo[4,5-d]pyrimidine, 19–21, ring system have been prepared by the direct alkylation of the sodium salt of the appropriate aglycon with the respective alkylbromides. Dehydra-tive coupling of 3-amino-6-hydrazino-1,2,4-triazin-5(4H)-one ( 22 ) with either hexanoic acid or heptanoic acid, and further ring closure of the reaction products 24a and 24b provided the n-pentyl and n-hexyl derivatives of 6-amino-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-one 25a and 25b , respectively. A similar condensation of 3-amino-6-aminomethyl-1,2,4-triazin-5(4H)-one ( 23 ) with heptanoic acid, followed by ring annulation, readily gave 2-amino-7-n-hexylimidazo[5,1-f][1,2,4]triazin-4(3H)-one ( 25c ). Bromination of 25c with N-bromosuccini-mide afforded the corresponding 5-bromo derivative 26 . Alkylation of the in situ generated sodium salt of 4-methoxycarbonylmethyl-5-methoxycarbonyl-2-oxo-1H,3H-imidazole ( 27 ) with 1-bromohexane gave the N-1 alkylated product 31 . Manipulation of the functional groups in 31 and further hydrazine mediated ring annulation furnished 5,6-diamino-1-n-hexyl-3-methylimidazo[4,5-c]pyridine-2,4-dione ( 39 ). Catalytic hydrogena-tion of 39 gave 7-methyl-8-oxo-9-hexyl-3-deazaguanine ( 40 ), a congener of the immunostimulator 7-methyl-8-oxoguanosine.     

Novel Synthesis and Structures of Amines and Triazole-Derived Glycoside and Nucleoside Derivatives of Phosphanyl Sugar Analogs

ABSTRACT

3-Methyl-1-phenyl-2-phospholene and 1-phenyl-2-phospholene 1-oxides were converted into 2-bromo-3-hydroxy-3-methyl-1-phenylphospholane and 2-bromo-3-hydroxy-1-phenylphospholane 1-oxide (1-bromo-1,3,4-trideoxy-1,4-C-[(R, S)-phenylphosphinylidene]-glycero-tetrofuranose) by the action of bromine in aqueous medium. The bromo substituent of the phospholane was substituted by treatment with amines or an azide anion to afford novel glycoside derivatives of phosphanyl sugar analogs such as 2-amino-3-hydroxy-1-phenylphospholane (3,4-dideoxy-1,4-C-[(R, S)-phenylphosphinylidene]-glycero-tetrofuranosylamine) and 2-azido-3-hydroxy-3-methyl-1-phenylphospholane 1-oxides with retention of the configuration. The 1,3-dipolar cycloaddition of the 2-azido derivative of the phospholane with alkynes gave 3-hydroxy-3-methyl-1-phenyl-2-(triazol-1′-y1)phospholane 1-oxides as a novel triazole-derived nucleoside of phosphanyl sugar analogs. The structure of the glycoside and nucleoside derivatives of the phosphanyl sugar analogs prepared was deterimined from IR, NMR, and X-ray crystallography analysis.     

A Facile and Efficient Synthesis of Novel 1,2,4-Triazolo[5,1- b ]quinazolin-9-one Derivatives

 A facile and efficient synthesis of a series of novel 1,2,4-triazolo[5,1-b]quinazolines is described. 2,3-Diaryl-2,3-dihydro-1H-1,2,4-triazolo[5,1-b]quinazolin-9-ones were obtained by reaction of 3-amino-2-arylamino-3H-quinazolin-4-ones with aromatic aldehydes as well as by ring closure of the corresponding anils. Treatment of 3-amino-2-arylamino-3H-quinazolin-4-ones with aromatic carboxylic acids afforded 2,3-diaryl-3H-1,2,4-triazolo[5,1-b]quinazolin-9-ones which could also be synthesized by dehydrogenation of the corresponding dihydro derivatives. Reaction of 3-amino-2-arylamino-3H-quinazolin-4-ones with diethyl malonate and acetylacetone gave 3-aryl-3,9-dihydro-9-oxo-1,2,4-triazolo[5,1-b]quinazolin-2-yl-acetic acid ethyl ester and 3-aryl-2-methyl-3H-1,2,4-triazolo[5,1-b]quinazolin-9-ones, respectively. The latter compounds were also prepared via reaction with acetic anhydride, whereas acetylation with acetic anhydride in the presence of pyridine afforded the acetyl derivatives.     

Synthesis of certain alkenyl purines and purine analogs

Synthesis of alkenyl derivatives of certain purines and purine analogs is described. Direct alkylation of the sodium salt of 6-chloropurine (1) either with 1-bromo-2-pentene or 4-bromo-2-methyl-2-butene in N,N-dimethylformamide furnished N-7, 4a and N-9, 3a , 3b alkenyl derivatives. Similar alkylation of 2-amino-6-chloropurine (2) provided the corresponding N-7, 4c-4e and N-9, 3c-3e alkenyl derivatives. Acid hydrolysis of these chloro derivatives 3a-3e, 4a,c-e furnished the corresponding alkenyl hypoxan-thines 6a, 6b and 7a or alkenyl guanines 6c-6e and 7c-7e. Treatment of 3a-3d with thiourea in absolute ethanol provided the corresponding 6-thio derivatives 5a-5d. Alkylation of the sodium salt of either purine-6-carboxamide (8) or 1,2,4-triazole-3-carboxamide (10) gave mainly one isomer 9a, 9b and 11a, 11b. The direct alkylation of pyrrolo[2,3-d]pyrimidin-4(3H)-one (12) gave N-3 alkenyl derivatives 13a, 13b , and the N-7 alkenyl derivatives 16a, 16b have been prepared starting from the 4-chloro derivative 14 . Synthesis of 2-amino-7-(2-penten-1-yl)pyrrolo[2,3-d]pyrimidin-4(3H)-one (19a) has been accomplished starting from 2-amino-4-methoxypyrrolo[2,3-d]pyrimidine (17) . These alkenyl derivatives were found to be devoid of anti-HCMV activity in vitro.     

A Facile and Efficient Synthesis of Novel 1,2,4-Triazolo[5,1-b]quinazolin-9-one Derivatives

Summary.  A facile and efficient synthesis of a series of novel 1,2,4-triazolo[5,1-b]quinazolines is described. 2,3-Diaryl-2,3-dihydro-1H-1,2,4-triazolo[5,1-b]quinazolin-9-ones were obtained by reaction of 3-amino-2-arylamino-3H-quinazolin-4-ones with aromatic aldehydes as well as by ring closure of the corresponding anils. Treatment of 3-amino-2-arylamino-3H-quinazolin-4-ones with aromatic carboxylic acids afforded 2,3-diaryl-3H-1,2,4-triazolo[5,1-b]quinazolin-9-ones which could also be synthesized by dehydrogenation of the corresponding dihydro derivatives. Reaction of 3-amino-2-arylamino-3H-quinazolin-4-ones with diethyl malonate and acetylacetone gave 3-aryl-3,9-dihydro-9-oxo-1,2,4-triazolo[5,1-b]quinazolin-2-yl-acetic acid ethyl ester and 3-aryl-2-methyl-3H-1,2,4-triazolo[5,1-b]quinazolin-9-ones, respectively. The latter compounds were also prepared via reaction with acetic anhydride, whereas acetylation with acetic anhydride in the presence of pyridine afforded the acetyl derivatives. Received March 22, 2001. Accepted (revised) May 11, 2001     

Bromination of N-(o-Aminophenyl)-cis-4-cyclohexene-1,2-dicarboximide and cis-2-(2-Benzimidazolyl)-4-cyclohexene-1-carboxylic Acid

Exhaustive oxidative bromination of N-(o-aminophenyl)-cis-4-cyclohexene-1'2-dicarboximide and2-(2-benzimidazolyl)-cis-4-cyclohexene-1-carboxylic acid results in bromine addition at the double bond.Under more severe conditions, the addition of bromine at the double bond is accompanied by bromination ofthe aromatic ring. The latter process does not occur in the exhaustive bromination of cis-2-(2-benzimidazolyl)-4-cyclohexene-1-carboxylic acid.     

Synthesis of New 2-[(Substituted-pyrazolin-1-yl)carbonyl]-thieno[2,3-b]pyridine Derivatives

The reaction of 3-amino-4,6-dimethyl-2-thieno[2,3-b]pyridine carbohydrazide ( 1 ) with appropriate chalcones 2a-2d in the presence of acid catalyst produced the corresponding 3-amino-2-[(3,5-disubstituted-pyrazolin-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 3a-3d . 3-Amino-2-[(3-substituted-pyrazolin-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 7a, 7b were also obtained by the cyclization reaction of carbohydrazide 1 with Mannich base derivatives 6a, 6b under basic condition.     

Synthesis of lipooligosaccharides related to nodulation factors ofRhizobium sp. NGR234

Trisaccharide analogs of natural nodulation factors fromRhizobium sp. NGR234, namely, 2-acetamido-2-deoxy-4-O-(2-deoxy-2-hexadecanamido-β-d-glucopyranosyl)-6-O-(2-O-methyl-α-l-fucopyranosyl)-d-glucopyranose and its derivatives containing a 4-O-acetyl or a 3-O-sulfo group at thel-fucose residue, were synthesized. The oligosaccharides synthesized were shown to posses biological activity. Laboratoire de Biologie Moléculaire des Plantes Supérieures (LBMPS), Université de Genève, 1 ch. de l'Impératrice, 1292 Chambesy-Genève, Suisse. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya No. 3, pp. 513–518, March, 1998.     

Coupling to the pyrimido[4,5-b][1,4]oxazine ring system: Synthesis of potential antifolates

The ability of 2-amino-4-hydroxy-7H-pyrimido[4,5-b][1,4]oxazine derivatives to inhibit dihydrofolate reductase led to a search for means of synthesizing new side chain substituted analogs of this marginally stable pyrimidooxazine system. A study of the synthesis and use of 6-functionalized pyrimido[4,5-b][1,4]oxazines for coupling side chains was begun and has now revealed methods for coupling p-aminobenzoic acid with 2-amino-4-hydroxy-6-carboxy-7H-pyrimido[4,5-b][1,4]oxazine and hydrolyzed 2-amino-4-hydroxy-6-carbe-thoxymethylene-6,7-dihdyro-5H-pyrimido[4,5-b][1,4]oxazine. The products are of interest for evaluation as potential antifolates.     

Herstellung von Dihydro-, Tetrahydro- und Hexahydrochelidamsäure-Derivaten

Preparation of dihydro-, tetrahydro- and hexahydro-chelidamic-acid derivatives. Three methods for the preparation of 4-oxo-2,6-piperidine-dicarboxylic acid ( 3 ) and derivatives, required as a synthon for betalaine pigments, were explored. The best method was found to be the catalytic hydrogenation of chclidamic acid ( 1 ) with 5% Rh/Alox in water under 2.7 atm. H₂ for 33 h at 70° and subsequent esterification with methanol which gave 42% of cis, cis-4-hydroxy-2,6-piperidine- ( 7 ) and 10% of 2,6-cis-piperidine-dicarboxylic acid dimethyl ester ( 8 ), readily separable by chromatography. Oxidation of 7 with dimethylsulfoxide and a carbodiimide attached to a polymer afforded 90% of 4-oxo-2,6-cis-piperidine-dicarboxylic acid dimethyl ester ( 19 ). Other methods of oxydizing 7 to 19 were less successful. The electrochemical reduction of 1 followed by esterification with methanol led in a low yield to a mixture of 4-oxo-0-2,6-trans-piperidine-dicarboxylic acid dimethylester ( 24 ), its dimethyl acetal 25 and presumably trans-4-hydroxy-r-2, cis-6-piperidine-dicarboxylic acid dimethyl ester ( 26 ). Reaction of 4-oxo-hepta-2E, 5E-dienoic acid ( 35 ) with aqueous ammonia gave a 98% yield of a 3 : 2 mixture of cis- and trans-ammonium-4-oxo-2, 6-piperidine-dicarboxylate ( 39 and 40 ). The above mentioned catalytic hydrogenation method was also applied to N-ethyl-chelidamic acid ( 16 ) to give a 4:6 mixture of the N-ethyl derivatives 17 and 18 . Furthermore, a number of functional derivatives of 5 , of 19 , of 39 and of 40 were prepared. Oxidation of the hydroxy-diester 7 with dimethylsulfoxide and a carbodiimidc derivative in the presence of trifluoroacetic acid afforded 4-oxo-1,2,3,4-tetrahydro-2, 6-pyridine-dicarboxylic acid dimethyl ester ( 50 ). This ester was also obtained under the same conditions from thc keto-diester 19 .     

Synthesis and characterization of azo-linked Schiff bases and their nickel(II), copper(II), and zinc(II) complexes

Azo compounds were prepared by coupling of benzenediazonium chloride ions with 1-amino-2-hydroxy-4-naphthalene sulfonic acid under alkaline conditions, and Schiff bases, L_1–3 were then obtained by the condensation of 1-amino-2-hydroxy-3-(phenylazo)-4-naphthalene sulfonic acid, 1-amino-2-hydroxy-3-(4-ethylphenylazo)-4-naphthalene sulfonic acid, and 1-amino-2-hydroxy-3-(4-nitrophenylazo)-4-naphthalene sulfonic acid with salicylaldehyde. New copper(II), nickel(II), and zinc(II) complexes of the Schiff base ligands were also prepared and characterized by spectroscopic methods, magnetic measurements, elemental, and thermogravimetric analysis.     

Condensed Isoquinolines. 12. Synthesis of Novel Heterocyclic Systems Containing a Partially Hydrogenated Spiro[isoquinoline-4,4'-(2H)-pyran] Fragment

By condensation of 4-(2-bromomethyl)-3,4,5,6-tetrahydro-2H-pyran-4-carbonitrile with anthranilic acid, its derivatives substituted in the benzene ring (esters, nitrile), and with esters of 2-aminothiophene-3-carboxylic acids and 3-amino-5-bromobenzofuran-2-carboxylic acid there have been synthesized novel derivatives which include spiro-linked tetrahydropyran and 5,10-dihydro-3H-pyrimido[1,2-b]isoquinoline fragments. The pyrimidine ring of the latter was annelated by a substituted benzene, thiophene, or 5-bromobenzofuran ring.     

Synthesis of 10-thia-5-deazafolic acid and 2-desamino-2-oxo-10-thia-5-deazafolic acid

The folate analogue, 10-thia-5-deazafolic acid, was obtained via a multistep synthetic sequence beginning with the known intermediate, 2,4-diaminopyrido[2,3-d]pyrirnidine-6-carboxaldehyde. Reduction of this aldehyde with sodium borohydride gave 2,4-diamino-6-(hydroxymethyl)pyrido[2,3-d]pyrimidine, which when heated in base gave 2-amino-3,4-dihydro-6-(hydroxymethyl)-4-oxopyrido[2,3-d]pyrimidine. Treatment of the latter compound with phosphorus tribromide in tetrahydrofuran afforded 2-amino-6-(bromomethyl)-3,4-dihydro-4-oxopyrido[2,3-d]pyrimidine, thus constituting the first successful synthesis of this elusive intermediate. The aforementioned bromomethyl compound reacted smoothly with the sodium salt of ethyl 4-mercaptobenzoate, and the resulting ester was saponified to give 10-thia-5-deazapteroic acid. Conventional peptide bond coupling to di-tert-butyl L-glutamate followed by treatment with trifluoroacetic acid afforded the target compound in respectable yield. Attempts to prepare its 5,6,7,8-tetrahydro derivative by catalytic hydrogenation were unsuccessful.     

Tilted amides in amino acid and peptide derivatives

Background: Amide bonds in peptides and proteins typically adopt planar cis or trans conformations. Conversions between cis and trans amide conformations are necessary for protein folding and for many other processes, but are difficult to achieve since they involve disruption of the planarity of the bond. As a first step to understanding cis-trans isomerization, we set out to synthesize and characterize peptides that mimic the tilted or twisted amide structures that are postulated to form the intermediate states in this process.Results: We have synthesized a model amino acid and four dipeptide derivatives containing a methyl-substituted aziridine residue. Single crystals of phenacyl (2R, 3R)-benzyloxycarbonyl-3-methyl-2-aziridinecarboxylate and phenacyl (2R, 3R)-acetyl-glycyl-3-methyl-2-aziridine-carboxylate were obtained. Using X-ray diffraction analysis, we determined that the amide nitrogens of the aziridine rings have tetrahedral sp³-like geometry with tilt angles in the range of 37–38°. The ¹³C-NMR spectra indicate that the amide carbonyl is dramatically shifted downfield as a consequence of the tilt.Conclusions: In peptides containing a substituted aziridine ring, the orbitals of the amide nitrogen are constrained into a tilted configuration. These peptides may mimic the transition state between cis and trans amide conformations. This technique thus provides a novel strategy for the study of isomerization and other biorecognition processes.     

Investigation of the reaction products of 5-amino-1,3-disubstituted-pyrazoles with aromatic aldehydes. synthesis of new fluorinated 1,3,4-trisubstituted-4H-pyrazolo[3,4-e][1,4]thiazepin-7-ones

The condensation products of 5-amino-1,3-disubstituted-pyrazoles with aromatic aldehydes were identified as 2,4-dihydro-2,5-diphenyl-4-(phenylmethylene)-3H-pyrazol-5-imine derivatives Treatment of these products with mercaptoacetic acid gave new fluorine containing 1H-pyrazolo[3,4-e][1,4]thiazepin-7-ones.     

Die absolute Konfiguration der 3,5-Diaminohexansäure aus der β-Lysin-Mutase-Reaktion

Absolute configuration of the 3,5-diaminohexanoic acid produced in the β-lysine mutase reaction The (3S, 5S)-configuration of the 3,5-diaminohexanoic acid 3 produced by the coenzyme-B₁₂-dependent β-lysine mutase from Clostridium sticklandii has been determined by two different methods: by comparison of the ¹H-NMR.-spectrum of its δ-lactam with that of synthetic (±)-cis-and (±)-trans-4-amino-6-methyl-piperidones ( 1 and 2 ) and by chemical correlation with (+)-(6S)-6-methyl-piperidone-2 ( 9 ).