Novel derivatives of guanine

Claim 1

A method for the preparation of a compound of the formula wherein each of R 1 and R 2 , which are the same or different, is hydrogen, hydroxy or fluoro: provided that R 1 or R 2 is hydrogen when R 1 and R 2 are different, and provided that R 1 and R 2 are hydroxy or fluoro when R 1 and R 2 are the same; or a physiologically acceptable salt or an optical isomer, comprising: A. Reducing a compound of the formula wherein R 1 and R 2 have the meaning given above, and wherein R is hydrogen, alkyl containing 1-8 carbon atoms, substituted or unsubstituted phenyl, or benzyl; B. Hydrolysing a compound of the formula wherein R 1 and R 2 have the meaning given above,X 1 is a leaving group such as chlorine, bromine, iodine or a group -SH, -OR 2 , -SR 2 or -SO 2 R 2 in which formulas R 2 is alkyl containing 1-8 carbon atoms, fluorinated alkyl containi.ng 1-8 carbon atoms, alkylaryl such as benzyl, or aryl; Cl.Hydrolysing a compound of the formula wherein Y is OH or a group X 1 as defined in method B, and R 3 , R4, R 5 and R 6 are the same or different and are hydrogen, -COR 2 , or -SO 2 R 2 wherein R 2 is as defined in method B; C2. Hydrolysing a compound of the formula IV in method Cl wherein additionally R 3 and R 4 together, or R 3 and R 5 together form a cyclic ketal as defined in method L 3 or a cyclic carbonate ester. D. Hydrolysing a compound of the formula wherein Y and R 6 are as defined in method C and Z 1 , Z 2 and Z 3 are the same or different and are halogen such as chlorine, bromine or iodine, or groups OR 3 , OR 4 or OR 5 as defined in method Cl or in method C2; to the formation of a compound of the formula I wherein at least one of R 1 and R 2 is hydroxy; E. Hydrolysing a compound of the formula wherein R 7 is a silyloxy group such as trimethylsilyloxy or tert.-butyldiphenylsilyloxy or a group Y as defined in method C1, and R 8 , R 9 , and R 10 are the same or different and are silyl groups such as trimethylsilyloxy or tert.- butyldiphenylsilyloxy or groups Z 1 ,Z 2 and Z 3 respectively as defined in method D; and R 11 is a silyl group such as trimethylsilyl or tert.-butyldiphenylsilyl or a group R 6 as defined in method C. F. Ring-closure of a compound of the formula wherein R 7 , R 8 , R 9 , R 10 and R 11 are as defined in method E, by reaction with formic acid or a derivate thereof such as an arthoformate ester, followed by hydrolysis of the groups R 7 -R 11 as described in method E; G. Condensation of a compound of the formula with a compound of the formula wherein R 7 -R 11 are as defined in method E and X 2 is a leaving group such as chlorine, bromine, iodine or a group SO 2 R 2 where R 2 is as defined in method B, followed by hydrolysis of the groups R 7 -R 11 as described in method E; H. Vicinal dihydroxylation of the compound of the formula wherein R 7 , R 10 and R 11 are as defined in method E,followed by hydrolysis of the groups R 7 ,R 10 and R 11 as described in method E, to the formation of a compound of the formula I wherein R 1 and R 2 are hydroxy; I. Hydrolysing the compound of the formula wherein R 7 , R 10 and R 11 are as defined in method E,followed by hydrolysis of the groups R 7 ,R 10 and R 11 as described in method E, to the formation of a compound of the formula I wherein R 1 and R 2 are hydroxy; K. Condensation of a compound of the formula with a compound of the formula wherein R 7 , R 10 and R 11 are as defined in method E, followed by hydrolysis of the groups R 7 , R 10 and R 11 as described in method E, to the formation of a compound of the formula I wherein R 1 is hydroxy and R 2 is hydrogen. L. Condensation of a compound of the formula in which formulas R 1 is as defined in method A, R 12 is alkoxy containing 1-8 carbon atoms or R l ; R 7 and R 11 are as defined in method E and X 2 is as defined in method G, to the formation of a compound of the formula I wherein R 1 or R 2 is hydroxy; or a derivative thereof which can be transformed to said compound according to methods known per se; N. Reduction of a compound of the formula wherein R 1 is as defined in method A, to the formation of a compound of the formula I wherein either R 1 or R 2 is hydroxy; N. Hydroboration of a compound of the formula wherein R 7 , R 10 and R 11 are as defined in method E, followed by hydrolysis of the groups R 7 ,R 10 and R 11 as described in method E, to the formation of a mixture of the compounds of the formula I wherein either R 1 or R 2 is hydroxy; 0. Reduction of a compound of the formula wherein R 7 , R 10 and R 11 are as defined in method E,followed by hydrolysis of the groups R 7 ,R 10 and R 11 as described in method E, to the formation of a compound of the formula I wherein at least one of R 1 and R 2 is fluorine; P. Fluorination of a compound of the formula wherein R 7 , R 10 and R 11 are as defined in method E to the formation of a compound of the formula I wherein at least one of R 1 and R 2 is fluorine, or a derivative thereof which can be transformed to said compound according to methods known per se; R. Substitution of leaving groups Z 1 and/or Z 2 with fluorine in a compound of the formula wherein Z 1 and Z 2 are as defined in method D, to the formation of a compound of the formula I wherein at least one of R 1 and R 2 is fluorine; S. Addition with fluorinating reagents to the isolated double bond in the compound of the formula wherein R 7 , R 10 and R 11 are as defined in method E, followed by hydrolysis of the groups R 7 , R 10 and R 11 as described in method E, to the formation of a compound of the formula I wherein at least one of R 1 and R 2 is fluorine; T. Hydroboration of a compound of the formula wherein R 7 and R 11 are as defined in method E,followed by hydrolysis of the groups R 7 and R 11 as described in method E, to the formation of a compound of the formula wherein R 1 is fluorine and R 2 is hydrogen; U. Substitution of amino for X 3 in a compound of the formula wherein R 1 and R 2 have the meaning given above and X 3 is a leaving group such as chlorine, bromine or iodine, to the formation of a compound of the formula I; V. Transformation of a compound of the formula wherein R 1 and R 2 have the meaning given above and R 10 is as defined in method E, followed by hydrolysis of the group R 10 as described in method E, to the formation of a compound of the formula I; W. Ring-closure of a compound of the formula wherein R 8 , R 9 and R 10 are as defined in method E, followed by hydrolysis of the groups R 8 , R 9 and R 10 as described in method E, to the formation of a compound of the formula I. X. Hydrplysing a compound of the formula wherein R 4 is as defined in method Cl and R 7 and R 11 are as defined in method E, to the formation of a compound of the formula I wherein R 1 and R 2 are hydroxy; whereupon optionally a base obtained is converted to a pharmaceutically acceptable salt or a salt obtained is converted to the base or to a different, pharmaceutically acceptable salt, and optionally an isomeric mixture obtained is separated to a pure enantiomeric isomer.

Claim 2

A method for the preparation of a compound of the formula wherein each of R 1 and R 2 , which are the same or different, is hydrogen, hydroxy or fluoro: provided that R 1 or R 2 is hydrogen when R 1 and R 2 are different, and provided that R 1 and R 2 are hydroxy or fluoro when R 1 and R 2 are the same; or a physiologically acceptable salt or an optical isomer, comprising: A. Reducing a compound of the formula wherein R 1 and R 2 have the meaning given above, and wherein R is hydrogen, alkyl containing 1-8 carbon atoms, substituted or unsubstituted phenyl, or benzyl; B. Hydrolysing a compound of the formula wherein R 1 and R 2 have the meaning given above,X 1 is a leaving group such as chlorine, bromine, iodine or a group -SH, -OR 2 , -SR 2 or -SO 2 R 2 in which formulas R 2 is alkyl containing 1-8 carbon atoms, fluorinated alkyl containi.ng 1-8 carbon atoms, alkylaryl such as benzyl, or aryl; Cl.Hydrolysing a compound of the formula wherein Y is OH or a group X 1 as defined in method B, and R 3 , R4, R 5 and R 6 are the same or different and are hydrogen, -COR 2 , or -SO 2 R 2 wherein R 2 is as defined in method B; C2. Hydrolysing a compound of the formula IV in method Cl wherein additionally R 3 and R 4 together, or R 3 and R 5 together form a cyclic ketal as defined in method L 3 or a cyclic carbonate ester. D. Hydrolysing a compound of the formula wherein Y and R 6 are as defined in method C and Z 1 , Z 2 and Z 3 are the same or different and are halogen such as chlorine, bromine or iodine, or groups OR 3 , OR 4 or OR 5 as defined in method Cl or in method C2; to the formation of a compound of the formula I wherein at least one of R 1 and R 2 is hydroxy; E. Hydrolysing a compound of the formula wherein R 7 is a silyloxy group such as trimethylsilyloxy or tert.-butyldiphenylsilyloxy or a group Y as defined in method C1, and R 8 , R 9 , and R 10 are the same or different and are silyl groups such as trimethylsilyloxy or tert.- butyldiphenylsilyloxy or groups Z 1 ,Z 2 and Z 3 respectively as defined in method D; and R 11 is a silyl group such as trimethylsilyl or tert.-butyldiphenylsilyl or a group R 6 as defined in method C. F. Ring-closure of a compound of the formula wherein R 7 , R 8 , R 9 , R 10 and R 11 are as defined in method E, by reaction with formic acid or a derivate thereof such as an arthoformate ester, followed by hydrolysis of the groups R 7 -R 11 as described in method E; G. Condensation of a compound of the formula with a compound of the formula wherein R 7 -R 11 are as defined in method E and X 2 is a leaving group such as chlorine, bromine, iodine or a group SO 2 R 2 where R 2 is as defined in method B, followed by hydrolysis of the groups R 7 -R 11 as described in method E; H. Vicinal dihydroxylation of the compound of the formula wherein R 7 , R 10 and R 11 are as defined in method E,followed by hydrolysis of the groups R 7 ,R 10 and R 11 as described in method E, to the formation of a compound of the formula I wherein R 1 and R 2 are hydroxy; I. Hydrolysing the compound of the formula wherein R 7 , R 10 and R 11 are as defined in method E,followed by hydrolysis of the groups R 7 ,R 10 and R 11 as described in method E, to the formation of a compound of the formula I wherein R 1 and R 2 are hydroxy; K. Condensation of a compound of the formula with a compound of the formula wherein R 7 , R 10 and R 11 are as defined in method E, followed by hydrolysis of the groups R 7 , R 10 and R 11 as described in method E, to the formation of a compound of the formula I wherein R 1 is hydroxy and R 2 is hydrogen. L. Condensation of a compound of the formula in which formulas R 1 is as defined in method A, R 12 is alkoxy containing 1-8 carbon atoms or R l ; R 7 and R 11 are as defined in method E and X 2 is as defined in method G, to the formation of a compound of the formula I wherein R 1 or R 2 is hydroxy; or a derivative thereof which can be transformed to said compound according to methods known per se; N. Reduction of a compound of the formula wherein R 1 is as defined in method A, to the formation of a compound of the formula I wherein either R 1 or R 2 is hydroxy; N. Hydroboration of a compound of the formula wherein R 7 , R 10 and R 11 are as defined in method E, followed by hydrolysis of the groups R 7 ,R 10 and R 11 as described in method E, to the formation of a mixture of the compounds of the formula I wherein either R 1 or R 2 is hydroxy; 0. Reduction of a compound of the formula wherein R 7 , R 10 and R 11 are as defined in method E,followed by hydrolysis of the groups R 7 ,R 10 and R 11 as described in method E, to the formation of a compound of the formula I wherein at least one of R 1 and R 2 is fluorine; P. Fluorination of a compound of the formula wherein R 7 , R 10 and R 11 are as defined in method E to the formation of a compound of the formula I wherein at least one of R 1 and R 2 is fluorine, or a derivative thereof which can be transformed to said compound according to methods known per se; R. Substitution of leaving groups Z 1 and/or Z 2 with fluorine in a compound of the formula wherein Z 1 and Z 2 are as defined in method D, to the formation of a compound of the formula I wherein at least one of R 1 and R 2 is fluorine; S. Addition with fluorinating reagents to the isolated double bond in the compound of the formula wherein R 7 , R 10 and R 11 are as defined in method E, followed by hydrolysis of the groups R 7 , R 10 and R 11 as described in method E, to the formation of a compound of the formula I wherein at least one of R 1 and R 2 is fluorine; T. Hydroboration of a compound of the formula wherein R 7 and R 11 are as defined in method E,followed by hydrolysis of the groups R 7 and R 11 as described in method E, to the formation of a compound of the formula wherein R 1 is fluorine and R 2 is hydrogen; U. Substitution of amino for X 3 in a compound of the formula wherein R 1 and R 2 have the meaning given above and X 3 is a leaving group such as chlorine, bromine or iodine, to the formation of a compound of the formula I; V. Transformation of a compound of the formula wherein R 1 and R 2 have the meaning given above and R 10 is as defined in method E, followed by hydrolysis of the group R 10 as described in method E, to the formation of a compound of the formula I; W. Ring-closure of a compound of the formula wherein R 8 , R 9 and R 10 are as defined in method E, followed by hydrolysis of the groups R 8 , R 9 and R 10 as described in method E, to the formation of a compound of the formula I. X. Hydrplysing a compound of the formula wherein R 4 is as defined in method Cl and R 7 and R 11 are as defined in method E, to the formation of a compound of the formula I wherein R 1 and R 2 are hydroxy; whereupon optionally a base obtained is converted to a pharmaceutically acceptable salt or a salt obtained is converted to the base or to a different, pharmaceutically acceptable salt, and optionally an isomeric mixture obtained is separated to a pure enantiomeric isomer.

Claim 4

A method according to claim'l for the preparation of the compound 9-(2,4-dihydroxybutyl)guanine.

Claim 9

A method according to one of claims 1,2,3,4,5,6 or 7 for the preparation of an optical isomer of the final product.

Claim 10

A method according to one of claims 1,2,3,4,5,6 or 7 for the preparation of a physiologically acceptable salt of the final product.