Scripps Clinic and Research Foundation

The Scripps Research Institute

Michael G Goodman

William O Weigle

Robert H Chen

Allen B Reitz

Bruce E Maryanoff

Lawrence D Piro

Edward P Gamson

Immunostimulating 7,8-disubstituted guanine derivatives that also contain a 9-alkyl, 9-alkoxy or 9-aralkyl substituent are disclosed whose structures are represented by Formula I ##STR1## wherein X is O or S; R.sup.1 is a hydrocarbyl or substituted hydrocarbyl group having a length of about one to about seven carbon atoms; R.sup.2 is a hydrocarbyl or hydroxyl- or ether-substituted hydrocarbyl group having a length of about four to about ten carbon atoms; and the pharmaceutically acceptable base addition salts thereof. Also disclosed are compositions containing an immunostimulating guanine derivative and processes for using the same.

N.sup.9 alkyl or aralkyl derivatives of 7, 8-disubstituted guanines

Processes for the killing of cancerous B cells, and particularly chronic lymphocytic leukemia (CLL) cells are disclosed. In one process, cancerous B cells that do not proliferate when contacted with an immune response-enhancing agent are contacted with an amount of such an agent sufficient to cause peripheral CLL cells to undergo blast transformation and proliferation. The contacted cells are then maintained for a time period sufficient for them to die from that contact. Further contacting of those cells with a cytotoxic amount of an anti-cancer drug or cytotoxic conjugate enhances the death of those cancer cells. In another process, peripheral CLL cells that proliferate on contact with an immune response-enhancing-agent are contacted with a proliferation-inducing amount of such an agent. The contacted cells are maintained for a time period sufficient to undergo blast transformation and proliferation, and the blasts are then contacted with a cytotoxic amount of an anti-cancer drug or cytotoxic conjugate and maintained.

Cancerous B cell treatment using substituted nucleoside derivatives

Immunostimulating 7,8-disubstituted guanine derivatives that also contain a .beta.-9,1'-linked-2',3'-dideoxy-2',3'-didehydroribosyl substituent are disclosed whose structures are represented by Formula I ##STR1## wherein X is O or S; R.sup.1 is a hydrocarbyl or substituted hydrocarbyl moiety having a length of about one to about seven carbon atoms; R.sup.2 is hydrogen or C.sub.1 -C.sub.8 acyl; and the pharmaceutically acceptable base addition salts thereof. Also disclosed are compositions containing an immunostimulating guanine derivative and processes for using the same.

2'3'-dideoxy-2',3'-didehydro-7,8-disubstituted guanosines and their

Immunostimulating 7,8-disubstituted guanine derivatives that also contain a morpholinyl group as a position-9 substituent are disclosed whose structures are represented by formula I ##STR1## wherein X is O or S; R.sup.1 is a hydrocarbyl or substituted hydrocarbyl group having a length of about one to about seven carbon atoms; R.sup.2 is a hydrogen or C.sub.1 -C.sub.8 acyl; R.sup.3 is hydrogen, a C.sub.1 -C.sub.5 aliphatic hydrocarbyl, aralkyl or substituted aralkyl group; and the pharmaceutically acceptable base addition salts thereof. Also disclosed are compositions containing an immunostimulating substituted guanine derivative and processes for using the same.

Use of N9 morpholino derivatives of 7,8-disubstituted guanines

N9 morpholino derivatives of 7,8-disubstituted guanines

Compositions and methods for their use in modulating animal cellular responses are disclosed. The compositions include as an active agent an effective amount of an 8-substituted guanine derivative bonded 9-1' to an aldose having 5 or 6 carbon atoms in the aldose chain. The composition includes a diluent amount of a physiologically tolerable carrier. The guanine derivative is free of electrically charged functionality, while the 8-substituent has an electron withdrawing inductive effect greater than that of hydrogen and contains fewer than about 15 atoms. Animal cellular responses are modulated by contacting the cells with a composition of this invention.

Modulation of animal cellular responses with compositions containing

An immune response-enhancing guanosine analog derivative having a structure that conforms to the formula ##STR1## wherein Z is oxygen (O) or sulfur (S); X is oxygen (O), sulfur (S) selenium (Se) or cyanimino (NCN); and R.sub.1 is an aldoglycoside is disclosed. Also disclosed are a composition containing the guanosine analog derivative as active ingredient and a method of using the composition for immunostimulation.

Immunostimulating 7-deaza-7-oxa- and 7-deaza-7-oxo-analogs of

Compositions and methods for their use in modulating animal cellular responses are disclosed. The compositions include as an active agent an effective amount of an 8-substitued guanine derivative bonded 9-1' to an aldose having 5 or 6 carbon atoms in the aldose chain. The composition includes a diluent amount of a physiologically tolerable carrier. The guanine derivative is free of electrically charged functioinality, while the 8-substituent has an electron withdrawing inductive effect greater than that of hydrogen and contains fewer than about 15 atoms. Animal cellular responses are modulated by contacting the cells with a composition of this invention.

7,8-Disubstituted guanosine nucleoside derivatives are found to be potent immune response enhancing agents in human and animal cells. 7-Substituents are heteroatom-substituted-hydrocarbyl radicals having a length greater than ethyl and less than about decyl. 8-Substituents are .dbd.O, .dbd.S, .dbd.Se and .dbd.NCN. Compositions and methods of use are also disclosed.

Immunostimulating guanosine derivatives and their pharmaceutical

Compositions and methods for their use in modulating animal cellular responses are disclosed. The compositions include as an active agent an effective amount of an 8-substituted guanine derivative bonded 9-1' to an aldose having 5 or 6 carbon atoms in the aldose chain. The composition includes a diluent amount of a physiologically tolerable carrier. The guanine derivative is free of electrically charged funtionality, while the 8-substituent has an electron withdrawing inductive effector greater than that of hydrogen and contains fewer than about 15 atoms. Anmimal cellular responses are modulated by contacting the cells with a composition of this invention.

An antimicrobial composition and its method of use are disclosed. The composition contains an in vivo effective amount of an antibiotic and a potentiating amount of an immune response-enhancing agent. The immune response-enhancing agent corresponds in structure to a formula selected from ##STR1## where X is O or S; Z is N--R.sub.2, O or S; R.sub.1, R.sub.2 and R.sub.3 are substituted groups; and R.sub.4 is an aldoglycosidyl radical.

Growing community of inventors

Rancho Santa Fe, CA, United States of America

Michael G Goodman