Synthesis and Cytostatic Activity of N-[2-(Phosphonomethoxy)alkyl] Derivatives of N6-Substituted Adenines, 2,6-Diaminopurines and Related Compounds

2001 ◽  
Vol 66 (10) ◽  
pp. 1545-1592 ◽  
Author(s):  
Antonín Holý ◽  
Ivan Votruba ◽  
Eva Tloušťová ◽  
Milena Masojídková
Keyword(s):  
Cytostatic Activity ◽  
Secondary Amines ◽  
Dimethylformamide Dimethylacetal ◽  
Alkyl Derivatives ◽  
Derivatives Of ◽  
Related Compounds ◽  
Substituted Adenines

N6-Substituted adenine and 2,6-diaminopurine derivatives of 9-[2-(phosphonomethoxy)- ethyl] (PME), 9-[(R)-2-(phosphonomethoxy)propyl] [(R)-PMP] and enantiomeric (S)-PMP series were synthesized by reactions of primary or secondary amines with 6-chloro-9-{[2-(diisopropoxyphosphoryl)methoxy]alkyl}purines (26-28) or 2-amino-6-chloro-9-{[2-(diisopropoxy- phosphoryl)methoxy]alkyl}purines (29-31) followed by treatment of the diester intermediates32with bromo(trimethyl)silane and hydrolysis. Diesters32were also obtained by reaction ofN6-substituted purines with synthons23-25bearing diisopropoxyphosphoryl group. Alkylation of 2-amino-6-chloropurine (9) with diethyl [2-(2-chloroethoxy)ethyl]phosphonate (148) gave the diester149which was analogously converted toN6-substituted 2,6-diamino- 9-[2-(2-phosphonoethoxy)ethyl]purines151-153. Alkylation ofN6-substituted 2,6-diaminopurines with (R)-[(trityloxy)methyl]oxirane (155) followed by reaction of thus-obtained intermediates156with dimethylformamide dimethylacetal and condensation with diisopropyl [(tosyloxy)methyl]phosphonate (158) followed by deprotection of the intermediates159gaveN6-substituted 2,6-diamino-9-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]purines160-163. The highest cytostatic activityin vitrowas exhibited by the followingN6-derivatives of 2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine (PMEDAP): 2,2,2-trifluoroethyl (53), allyl (54), [(2-dimethylamino)ethyl] (68), cyclopropyl (75) and dimethyl (91). In CCRF-CEM cells, the cyclopropyl derivative75is deaminated to the guanine derivative PMEG (3) which is then converted to its diphosphate.

Synthesis of Optically Active N6-Alkyl Derivatives of (R)-3-(Adenin-9-yl)-2-hydroxypropanoic Acid and Related Compounds

2003 ◽  
Vol 68 (5) ◽  
pp. 931-950 ◽  
Author(s):  
Marcela Krečmerová ◽  
Miloš Buděšínský ◽  
Milena Masojídková ◽  
Antonín Holý
Keyword(s):  
Nmr Spectra ◽  
Enantiomeric Purity ◽  
Optically Active ◽  
Secondary Amines ◽  
H Nmr ◽  
Alkyl Derivatives ◽  
Optically Pure ◽  
Derivatives Of ◽  
Related Compounds

Reaction of ethyl (R)-oxiranecarboxylate (2a) with various nucleobases (adenine, 6-chloropurine, thymine, cytosine, N6-benzoyladenine, 4-methoxy-5-methylpyrimidin-2(1H)-one and 4-methoxypyrimidin-2(1H)-one) afforded ethyl 3-substituted-2-hydroxypropanoates 4-10. Enantioselectivity of this reaction is dependent on the type of the base: 6-chloropurine, N6-benzoyladenine, 4-methoxy-5-methylpyrimidin-2(1H)-one, thymine and cytosine gave optically pure R enantiomers. In other cases, partial or complete racemization occurred. Optically pure ethyl (R)-3-(6-chloropurin-9-yl)-2-hydroxypropanoate (5a) was hydrolyzed to give (R)-3-(6-chloropurin-9-yl)-2-hydroxypropanoic acid (11). Reactions of 11 with various primary or secondary amines led to N6-substituted (R)-3-(adenin-9-yl)-2-hydroxypropanoic acids 14-19. Enantiomeric purity was determined from 1H NMR spectra measured in the presence of (-)-(R)-1-(9-anthryl)-2,2,2-trifluoroethan-1-ol.

Synthesis of N9- and N7-[2-Hydroxy-3-(phosphonomethoxy)propyl] Derivatives of N6-Substituted Adenines, 2,6-Diaminopurines and Related Compounds

2004 ◽  
Vol 69 (10) ◽  
pp. 1889-1913 ◽  
Author(s):  
Marcela Krečmerová ◽  
Milena Masojídková ◽  
Antonín Holý
Keyword(s):  
Acetic Acid ◽  
Secondary Amines ◽  
Phosphonic Acids ◽  
Purine Bases ◽  
Subsequent Hydrolysis ◽  
Catalyzed Reactions ◽  
Derivatives Of ◽  
Related Compounds ◽  
Substituted Adenines

Base-catalyzed reactions of diethyl [(oxiranylmethoxy)methyl]phosphonate (2) with purine bases (adenine, 2,6-diaminopurine, 6-chloropurine and 2-amino-6-chloropurine) gave corresponding 9- or 7-[2-hydroxy-3-(phosphonomethoxy)propyl] purines. The adenine and 2,6-diaminopurine derivatives cyclize to cyclic phosphonates 4 and 6. The 9-[2-hydroxy-3-(phosphonomethoxy)propyl] derivatives of N6-substituted adenine and 2,6-diaminopurine (15-27) were prepared by the treatment of diethyl {[3-(6-chloropurin-9-yl)-2-hydroxypropoxy]methyl}phosphonate (11) or diethyl {[3-(2-amino-6-chloropurin-9-yl)-2-hydroxypropoxy]methyl}phosphonate (13) with primary or secondary amines. The reaction of 6-chloro- or 2-amino-6-chloropurine derivatives (11, 13) with thiourea gave the corresponding diethyl purine-6-thiol or 2-aminopurine-6-thiol phosphonates 47, 48. The guanine derivative 49 was prepared by the treatment of compound 13 with 80% acetic acid. All diethyl phosphonates were transformed to free phosphonic acids (31-43, 50-52) by the action of bromotrimethylsilane and subsequent hydrolysis.

N,N-Dialkyl-N′-Chlorosulfonyl Chloroformamidines in Heterocyclic Synthesis. Part XIV. Synthesis and Reactivity of the New Benzo[4,5]imidazo[1,2-b][1,2,6]thiadiazine Ring System

2018 ◽  
Vol 71 (1) ◽  
pp. 58 ◽  
Author(s):  
Dylan Innes ◽  
Michael V. Perkins ◽  
Andris J. Liepa ◽  
Craig L. Francis
Keyword(s):  
Medicinal Chemistry ◽  
Ring System ◽  
Heterocyclic Synthesis ◽  
Alkyl Derivatives ◽  
Regioselective Reactions ◽  
Novel Scaffold ◽  
Derivatives Of ◽  
Related Compounds

N,N-Dialkyl-N′-chlorosulfonyl chloroformamidines 1 underwent regioselective reactions with the 1,3-NCC bis-nucleophilic 1H-benzimidazole-2-acetonitriles 4 and related compounds to produce benzo[4,5]imidazo[1,2-b][1,2,6]thiadiazine dioxides 6, 9, 12, and 14, representatives of a new ring system. Reaction of dichlorides 1 with trifluoroacetyl derivative 16 afforded benzo[4,5]imidazo[1,2-c]pyrimidines 19 and 20. An N-acyl and some N-alkyl derivatives of benzimidazo-thiadiazines 6 were prepared to demonstrate the potential of this new ring system as a novel scaffold for synthetic and medicinal chemistry applications. Treatment of the 4-cyano-5-methyl-benzimidazo-thiadiazine 26c with LiAlH4 resulted in an unexpected and remarkable conversion of the nitrile to give the 4,5-dimethyl-benzimidazo-thiadiazine 29.

scholarly journals In Vitro Antiherpesviral Activity of 5-Alkyl Derivatives of 1- -D-Arabinofuranosyluracil

1979 ◽  
Vol 16 (2) ◽  
pp. 158-163 ◽  
Author(s):  
H. Machida ◽  
S. Sakata ◽  
A. Kuninaka ◽  
H. Yoshino ◽  
C. Nakayama ◽  
...  
Keyword(s):  
Alkyl Derivatives ◽  
Derivatives Of

Synthesis, Identification, and Acute Toxicity of Some 7V-AlkyI Derivatives of 3,4-Methylenedioxyamphetamine

1987 ◽  
Vol 70 (6) ◽  
pp. 981-986
Author(s):  
F Taylor Noggle ◽  
Jack Deruiter ◽  
Samuel T Coker ◽  
Randall C Clark
Keyword(s):  
Liquid Chromatography ◽  
Mobile Phase ◽  
Reductive Amination ◽  
Drugs Of Abuse ◽  
Mixture Toxicity ◽  
Secondary Amines ◽  
Reverse Phase ◽  
Alkyl Derivatives ◽  
Phase Mixture ◽  
Derivatives Of

Abstract A series of iV-alkyl derivatives of 3,4-methylenedioxyamphetamine (MDA) was prepared in an effort to characterize these potential drugs of abuse. These secondary amines were synthesized via reductive amination of the corresponding ketone with alkylamines. The ultraviolet absorption spectra for these compounds produced almost equally intense absorbance at 234 and 285 nm. The compounds were separated by liquid chromatography using reverse phase (c18) procedures with a ternary mobile phase mixture. Toxicity studies showed all of the compounds to have LDM values similar to A'-methyl MDA (MDMA).

Synthesis of Some 2'-C-Alkyl Derivatives of 9-(2-Phosphonomethoxyethyl)adenine and Related Compounds

1994 ◽  
Vol 59 (9) ◽  
pp. 2069-2094 ◽  
Author(s):  
Hana Dvořáková ◽  
Antonín Holý ◽  
Ivan Rosenberg
Keyword(s):  
Reaction Pathway ◽  
Sodium Hydride ◽  
Amino Group ◽  
Trimethylsilyl Derivative ◽  
Phosphonic Acids ◽  
Alkyl Derivatives ◽  
Hydrolysis Of ◽  
Trifluoromethyl Derivative ◽  
Derivatives Of ◽  
Related Compounds

To study the effect of β-substitution in 2'-alkyl derivatives of 9-(2-phosphonomethoxyethyl)adenine (Ia) on the antiviral activity or group specificity, these derivatives were synthesized. 9-(2-Hydroxyalkyl)adenines VIII were prepared by alkylation of adenine with suitably substituted oxiranes XIII or 2-hydroxyalkyl p-toluenesulfonates IV and VI. After protection of the adenine amino group by benzoylation (compounds IX) or amidine formation (compounds X), the intermediates were alkylated with diisopropyl p-toluenesulfonyloxymethanephosphonate (XI) in the presence of sodium hydride. After deprotection, the obtained phosphonate diesters XII were converted into phosphonic acids I by transsilylation and hydrolysis. This synthetic scheme was used for the preparation of ethyl (Ie), propyl (If), 2-propyl (Ig), 2-methylpropyl (Ih), cyclopropyl (Ii), cyclohexyl (Ij), benzyl (Ik) and phenyl (Il) derivatives. The 2'-trifluoromethyl derivative XXIIa was prepared analogously from 9-(2-hydroxy-3,3,3-trifluoropropyl)adenine (XXa), obtained by alkylation of adenine sodium salt with 2-hydroxy-3,3,3-trifluoropropyl bromide. 2'-Trimethylsilyl derivative XIXa was obtained by alkylation of adenine with 2-diisopropylphosphonomethoxy-3-(4-toluenesulfonyloxy)propyltrimethylsilane (XVII) followed by transsilylation and hydrolysis of diester XVIIIa. 2,6-Diaminopurine derivatives XVIIId and XXIIb were obtained analogously. 9-(3-Phosphonomethoxybutyl)adenine (XXVIII) and 9-(2-methyl-2-phosphonomethoxypropyl)adenine (XXXV) were prepared from the corresponding hydroxy derivatives XXVIb and XXXII, respectively, by the same reaction pathway as derivatives I.

N-sec- and N-tert-Alkyl derivatives of methoxamine and related compounds

1968 ◽  
Vol 11 (4) ◽  
pp. 833-844 ◽  
Author(s):  
Richard Baltzly ◽  
Nariman B. Mehta
Keyword(s):  
Alkyl Derivatives ◽  
Derivatives Of ◽  
Related Compounds

scholarly journals The binding of radioactive label from labelled phenacetin and related compounds to rat tissues in vivo and to nucleic acids and bovine plasma albumin in vitro

1971 ◽  
Vol 122 (3) ◽  
pp. 311-315 ◽  
Author(s):  
R. Nery
Keyword(s):  
Nucleic Acids ◽  
Rat Tissues ◽  
Biological Macromolecules ◽  
Plasma Albumin ◽  
Radioactive Label ◽  
Bovine Plasma ◽  
Derivatives Of ◽  
Related Compounds

1. acetyl-3H- and ethyl-14C-labelled derivatives of phenacetin and related compounds are described. 2. Radioactive label from the ethyl-14C-labelled derivatives of 4-nitrophenetole, 4-phenetidine and phenacetin binds in vitro to various extents to bovine plasma albumin, salmon sperm DNA and yeast RNA; the extent of binding is increased in the presence of a rat liver microsomal hydroxylating system and further increased when the microsomal enymes are induced by prior treatment of rats with 3-methylcholanthrene. 3. The ratios of the bound radioactive labels in vitro from [ethyl-14C]phenacetin, N-acetoxy[ethyl-14C]phenacetin, [acetyl-3H]phenacetin and [diacetyl-3H]N-acetoxyphenacetin per g-atom of DNA P, RNA P and per mol of protein in the absence of the microsomal system are approximately 1:60:11:863, 1:68:41:1835 and 1:88:713:2399 respectively. 4. Radioactive label from labelled phenacetin binds in vitro to all tissues examined, including the spleen, intestines, kidney and bladder; about 80% of the radioactivity bound to the liver is concentrated in the RNA and proteins. 5. Comparison of the relative extents of binding of radioactive label derived from equimolar amounts of labelled phenacetin, ethanol or acetate shows that the incorporation of labelled C2 units into tissues and biological macromolecules in vivo and in vitro may account for only a part of the total bound radioactive label derived from phenacetin and not at all from the incorporation of radioactive acetate into nucleic acids. 6. Some implications of these findings are discussed.

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