Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1990-10-31
1993-01-19
Rollins, John W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 26, 536 276, 514 45, 514 23, A61K 3170
Patent
active
051807149
DESCRIPTION:
BRIEF SUMMARY
orylase containing microorganism. Based on the respective abilities of 5-deoxy-5-(monofluoroethylthio)ribose (MFETR) and 5-deoxy-5-(hydroxyethylthio)ribose (HETR) to be converted, respectively to the identical, potentially toxic products, MFETR-1-P and HETR-1-P, in MTR kinase-containing organisms, the compounds HETR and MFETR would be the preferred effective agents for treating infections caused by MTR kinase-containing microorganisms.
The thioribose compounds of the invention, HETR, MFETR, CETR and BETR, may have utility as biocides against microorganisms which contain MTR kinase and which therefore have the ability to phosphorylate the thioribose.
Alternatively, the respective phosphates of the thioriboses may likewise be effective as biocides against microorganisms which lack MTR kinase and which therefore do not have the ability to phosphorylate the thioribose.
Pathogenic microorganisms known to contain MTR kinase include:
Giardia lamblia
Candida albicans
Staphyloccus aureus
Throughout this specification and claims, all temperatures are given in degrees Celsius and weights are given in grams, unless specified otherwise.
I. Preparation of the Compounds
The compound HETA can be produced in accordance with Kikugawa et al. in "Platelet Aggregation Inhibitors. 2. Inhibition of Platelet Aggregation by 5'-,2-,6-, and 8-Substituted Adenosines. J. Med. Chem. 15, 387, 1972. Certain improvements were made which improved the yield from about 50 percent to about 70 percent. Following is a description of the preferred method for producing HETA.
EXAMPLE A
Preparation of 5'-deoxy-5'-(hydroxyethylthio)adenosine (HETA)
Mercaptoethanol (8.83 ml) was added to a solution of NaOH (5.19 g) in water (27 ml). After stirring 0.5 hr, this mixture was added to a flask containing 5'-deoxy-5'-chloroadenosine (10 g) and the reaction mixture heated to 80 C on a hot plate with stirring for 2 hours. The flask was removed from the hot plate and allowed to stand at room temperature overnight or longer (3 days). A solidified precipitate remained in the flask, and water was added to facilitate its dissolution into a filterable precipitate. The product was filtered and washed with water. It was then recrystallized from water and the resulting, purified product, filtered and dried. Methanol was added to form a slurry which was then evaporated under vacuum to give 9.4 g HETA (81.8%); mp 190.degree.-192.degree. C. (softens at 120.degree. C.). Elemental analysis was correct for HETA.
When the general procedure of Kikugawa et al. was used, the reaction mixture was heated for one hour. Under these conditions, workup yielded a product which also contained unreacted starting material and which was then retreated with mercaptoethanol solution. Kikugawa's procedure was thus modified so that the reaction mixture was heated for two hours, thereby insuring completeness of reaction. The Kikugawa et al. procedure was modified by omitting the acidification step with acetic acid.
EXAMPLE B
Preparation of 5'-Deoxy-5'-(chloroethylthio)adenosine (CETA)
Thionyl chloride (3.7 ml, 4.3 g, 36.2 mM) was added to 31 ml hexamethylphosphoramide (HMPA) at 0.degree. with stirring, under nitrogen. After 30 minutes, HETA (4.0 g, 12.2 mM) in solid form, was introduced slowly to prevent clumping and stirring was continued an additional 2-4 hr at 0.degree. C. until thin layer chromatography (TLC) (CH.sub.2 Cl.sub.2/ MeOH; 21:4) indicated disappearance of starting material. The contents of the reaction flask were then poured onto an ice-water mixture (200 ml), to form a gummy residue, the pH was adjusted to 9 with ammonium hydroxide and the aqueous mixture was extracted 3 times with 200 ml portions of CH.sub.2 Cl.sub.2. The combined organic extracts were dried over MgSO.sub.4, filtered and evaporated to give an oil (1.9 g), which upon purification by silica gel column chromatography yielded 450 mg (11%) of CETA as a white solid. Elemental analysis was correct for the compound (C.sub.12 H.sub.16 N.sub.5 O.sub.3 ClS).
EXAMPLE C
Preparation of 5'-Deoxy-5'-(bro
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This invention was made under research grant 5U01-CA 37606 awarded by the National Cancer Institute of the National Institutes of Health of the U.S. Department of Health and Human Services, and research grant AI 17340 awarded by National Institutes of Health of the U.S. Department of Health and Human Services.
Bacchi Cyrus J.
Nathan Henry
Porter Carl W.
Spiess Arthur J.
Sufrin Janice R.
Crane L. Eric
Health Research , Inc.
Rollins John W.
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