9-substituted guanines

Details 9-substituted guanines 9-substituted guanines

1988-07-14

1990-04-10

Shah, Mukund J.

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen bonded directly to ring carbon of the purine ring...

C07D47318

Patent

active

049162250

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE ART

The present invention relates to organic chemistry and more particularly it relates to novel compounds, 9-substituted guanines. Said compounds have antiviral activity.


PRIOR ART

Known in the prior art are various compounds having antiviral properties, e.g. 9-[2-hydroxyethoxymethyl]-guanine with the formula ##STR2## which is the active principle of the medicinal preparation acyclovir produced by Welcome (DE, A, 2539963).
The preparation acyclovir as an efficacious antiviral preparation of the second generation acting on the virus of herpes simplex HSV-1 and HSV-2, and also on the virus of herpes zoster and other viruses of man and animal.
The preparation is however sparingly soluble in water (2 mg/ml) and is therefore hephrotoxic with oral administration.
When given intravenously, its infusion is prolonged (2 h). Intramuscular administration of acyclovir is infeasible because of its low solubility; if the preparation penetrates occasionally into the surrounding tissues during intravenous injections, the tissues become affected with necrosis due to the high alkaline reaction of the injection solution (pH 11.0).


DISCLOSURE OF THE INVENTION

The proposed compounds are entirely new and have not been described in the literature.
The object of the invention is to provide new compounds with antiviral activity and higher solubility in water and lipophilic substances of the body.
Said object has been accomplished by providing, according to the invention, new compounds, 9-substituted guanines, with the general formula ##STR3## where R' is acetyl or hydrogen, and
The proposed compounds are crystalline substances, the structure of which has been proved by the complex of the physicochemical properties given in Tables 1, 2.


TABLE 1 ______________________________________ Physicochemical properties of the proposed compounds ______________________________________ R.sub.f in system chloroform: Methyl M.p., alcohol Found, in % Compound .degree.C. (10:2) C H N ______________________________________ 9-[2-(2-tetrahydro- 162- 0.63 49.6 5.6 20.7 furyloxy)ethoxyme- 163 thyl]-N.sup.2 -acetyl- guanine 9-[2-(2-tetrahydro- furyloxy)ethoxymethyl] 192- 0.39 46.2 6.1 22.3 guanine 194 9-[2-(2-tetrahydro- pyranyloxy) ethoxy- methyl]-N.sup.2 -acetyl- 135- 0.66 51.1 6.0 19.7 guanine 136.5 ______________________________________ 1 2 3 4 5 6 ______________________________________ 9-[2-(2-tetrahydropy- ranyloxy)ethoxymethyl] guanine 202-204 0.44 50.3 6.3 22.4 ______________________________________ Calculated, in % Formula C H N 7 8 9 10 ______________________________________ C.sub.14 H.sub.19 N.sub.5 O.sub.5 49.8 5.7 20.8 C.sub.12 H.sub.17 N.sub.5 O.sub.4.H.sub.2 O 46.0 6.1 22.4 C.sub.15 H.sub.21 N.sub.5 O.sub.5 51.3 6.0 19.9 C.sub.13 H.sub.19 N.sub.5 O.sub.4 50.5 6.2 2.6 ______________________________________


TABLE 2 ______________________________________ Spectra of 9-substituted guanines U-V spectrum in PMR spectrum in dimethyl 0.01 M sulphoxide-d.sub.6 H.sub.3 BO.sub.3 (standard .lambda..sub.max tetramethyl- (.epsilon. .times. 10.sup.-3) silan), Compound in nm .delta. m.d. ______________________________________ 9-[ 2-(2-tetrahydro- 260(15.2) 12.01, 11.72(NH); furyloxy)ethoxymethyl]- -274(11.1) 8.10(H.sub.8); 5.46(NCH.sub.2); N.sup.2 -acetylguanine 5.02(CH); 3.60, 1.76 (CH.sub.2); 2.18(CH.sub.3) 9-[2-(2-tetrahydro- 253(10.4) 10.59(NH; 7.80(H.sub.8) furyloxy)ethoxymethyl] 270(7.5) 6.48(NH.sub.2); 5.33(NCH.sub.2); guanine 5.03(CH); 3.36, 1.76(CH.sub.2) 9-[2-(2-tetrahydro- 260(14.9) 11.99; 11.74(NH); pyranyloxy)ethoxyme- 276(10.7) 8.10(H.sub.8); 5.47(NCH.sub.2); thyl]-N.sup.2 -acetylguanine 4.49(CH); 3.61, 1.46 (CH.sub.2); 2.18(CH.sub.3) 9-[2-(2-tetrahydro- 253(10.5) 10.57(NH); 7.79(H.sub.8) pyranyloxy)ethoxy- 270(7.4) 6.47(NH.sub.2); methyl]guanine 5.34(NCH.sub.2); 5.11(CH); 3.62, 1.47(CH.sub.2) ______________________________________


MODE OF CARRYING OUT

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McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London & New York (1973), pp. 104-106.
Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York, (1981), p. 24.

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