Adenosine deaminase resistant antiviral purine nucleosides and method of preparation

• US 4,268,672 A
• Filed: 01/05/1979
• Issued: 05/19/1981
• Est. Priority Date: 02/09/1977
• Status: Expired due to Term

• Current Assignee: Regents of The University of Minnesota (University of Minnesota)
• Original Assignee: Regents of The University of Minnesota (University of Minnesota)
• Inventors: Vince, Robert
• Primary Examiner(s): Hollrah, Glennon H.
• Assistant Examiner(s): Eakin, M. C.
• Application Number:
  US06/001,072
• Time in Patent Office: 865 Days
• Field of Search: 544/264, 544/265, 544/277
• US Class Current: 544/265
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 303/36 with hydrocarbon radicals, substituted by nitrogen atoms nitro, nitroso radicals C07D303/08
• CPC Class Codes: C07D 473/00 Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine
• CPC Class Codes: C07D 473/38 attached in position 6
• CPC Class Codes: C07D 473/40 with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Abstract

The preparation of (±)-9-[α-(2α,3β-dihydroxy-4α-(hydroxymethyl)cyclopentyl)]-6-substituted purines: ##STR1## and (±)-3-[α-(2α,3β-dihydroxy-4α-(hydroxymethyl)cyclopentyl)]-7-substituted-v-triazolo[4,5d]pyrimidines: ##STR2## and their derivatives wherein R is amino, mercapto, methylmercapto, hydroxy, halogen, or substituted amino: ##STR3## wherein R'"'"' and R" may be the same or different and are of hydrogen, methyl, ethyl, propyl or phenyl. The preparation of the single intermediate from which either of these series of compounds may be synthesized is also disclosed. The compounds exhibit antiviral and antitumor activity. Acid salts and esters of the purine nucleosides have also been prepared.

Claims

1. A method of preparation of the purine nucleoside analog having the formula:

##STR9## wherein R is selected from the group of substituent groups consisting of amino, hydroxyl, mercapto, methylmercapto and substituted amino NR'"'"'R" wherein R'"'"' and R" may be the same or different and are hydrogen, methyl, ethyl, propyl or phenyl, which method comprises;

(A) preparing the intermediate ##STR10## wherein X is halogen, by (1) hydrolysing 2-azabicyclo[2.2.1]hept-5-en-3-one under acid conditions.

(2) esterifying the carboxyl function of the resulting cis-4-aminocyclo-pent-2-ene carboxylic acid salt,

(3) acetylating the amino group of the resulting ester,

(4) reducing and acetylating said ester,

(5) epoxidizing the resulting acetate,

(6) hydrolysing and acetylating the resulting epoxide,

(7) forming an amine from the resulting (±

)-4α

-acetamido-2β

, 3α

-diacetoxy-1α

-cyclopentanemethyl acetate, and

(8) condensing said amine with 5-amino-4,6-dihalopyrimidine to produce said intermediate;

(B) closing the ring of said intermediate by reaction with a ring closing agent selected from the class consisting of diethoxymethyl acetate and triethyl orthoformate, and

(C) replacing the halogen with a substituent from the group consisting of amino, hydroxyl, mercapto, methylmercapto and substituted amino.

2. A method according to claim 1 further characterized in that R is NH₂ and said halogen is replaced by reaction with ammonia.

3. A method according to claim 1 further characterized in that R is OH and said halogen is replaced by refluxing in aqueous acid.

4. A method according to claim 1 further characterized in that R is SH and said halogen is replaced by reaction with thiourea.

5. A method according to claim 1 further characterized in that R is SCH₃, said halogen is replaced by a mercapto group by reaction with thiourea and said mercapto is methylated by reaction with methyl iodide.