Antagonism of immunostimulatory CpG-oligonucleotides by 4-aminoquinolines and other weak bases
AssigneesUniversity of Iowa Research Foundation, Georgia State University Research Foundation, Inc., The United States of America as represented by the Department of Veterans Affairs
InventorsDonald E. Macfarlane, Lucjan Strekowski, Lori Manzel, Fyaz M. D. Ismail, Gordon B. Barlin
Life of this patent
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Abstract
The present invention relates generally to the field of immunology. More particularly it concerns compositions and methods for inhibiting stimulation of the immune system. The compounds and methods comprise compounds that are analogs and derivatives of chloroquine, such as 4-aminoquinolines, and other weak bases. They can be used in preventative and therapeutic treatments of autoimmune diseases and phenomena, transplant rejection such as host-versus-graft disease, and sepsis.
Claims49
A method of inhibiting immunostimulation in a subject, the method comprising administering an effective amount of a substituted 4-quinolinamine composition to said subject, the 4-quinolinamine composition comprising a compound having the structural formula A
- wherein
- RA is hydrogen atom or a lower alkyl group;
- RB is a substituted or unsubstituted alkyl, alkenyl or alkynyl secondary or tertiary amine;
- R2 is a unsubstituted or substituted phenyl group, a unsubstituted or substituted naphthyl group, an substituted or unsubstituted anthracyl group, a substituted or unsubstituted phenanthryl group or a substituted or unsubstituted styryl group;
- R3 is a hydrogen atom;
- R5 is a hydrogen atom;
- R6 is a hydrogen atom or a halogen atom;
- R7 is a hydrogen atom;
- and
- R8 is a hydrogen atom,
- and pharmaceutically acceptable salts thereof.
A method of inhibiting immunostimulation in a subject, the method comprising administering an effective amount of a substituted 4-quinolinamine composition to said subject, the 4-quinolinamine composition comprising a compound having the structural formula B
- wherein the phenyl group can be substituted at R9, R10, R11, R12 and R13, wherein said substituted phenyl group comprises one or more substitutions selected from the group consisting of an alkyl group, an alkoxy group, a hydroxy group, an alkylaminoalkyl group, an alkoxyalkyl group, an ester group, an alkylamino group, a dialkylamino group, a cyclic amino group, a furan group, a thiophene group, a halogen atom or any combination thereof;
- R2 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted anthracyl group, a substituted or unsubstituted styryl group or a substituted or unsubstituted phenanthryl group;
- R3 is a hydrogen atom;
- R5 is a hydrogen atom;
- R6 is a hydrogen atom or a halogen atom;
- R7 is a hydrogen atom, a halogen atom or an alkyl halogen atom;
- R8 is a hydrogen atom,
- and pharmaceutically acceptable salts thereof.
A method of inhibiting immunostimulation in a subject, the method comprising administering an effective amount of a substituted 4-quinolinamine composition to said subject, the 4-quinolinamine composition comprising a compound having the structural formula C
- wherein
- the phenyl group can be unsubstituted or substituted at R9, R10, R11, R12 and R13, wherein said substituted phenyl group comprises one or more substitutions selected from the group consisting of an alkyl group, an alkoxy group, an alkoxyalkyl group, an alkylaminoalkyl group, a hydroxy group, an ester group, an alkylamino group, an dialkylamino group, a cyclic amino group, a furan group, a thiophene group, a halogen atom, or any combination thereof;
- n is 0 to 4 CH2;
- R2 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted anthracyl group, a substituted or unsubstituted styryl group or a substituted or unsubstituted phenanthryl group;
- R3 is a hydrogen atom;
- R5 is a hydrogen atom;
- R6 is a hydrogen atom or a halogen atom;
- R7 is a hydrogen atom, a halogen atom or an alkyl halogen atom;
- R8 is a hydrogen atom,
- and pharmaceutically acceptable salts thereof.
A method of inhibiting immunostimulation in a subject, the method comprising administering an effective amount of a substituted bis-4-quinolinamine composition to said subject, the bis-4-quinolinamine composition comprising a compound having the structural formula D
- wherein
- RB on the first 4-quinolinamine is covalently attached to RB′ on the second 4-quinolinamine by linker group Y, wherein the linker group Y is an alkyl group, an ester group, an alkoxyalkyl group, an alkylamino group, an dialkylamino group, an amido group, a cyclohexane, a cyclohexanedieyl, a piperazino group, 1-4, piperazinedieyl, or any combination thereof;
- R2 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted anthracyl group, a substituted or unsubstituted styryl group or a substituted or unsubstituted phenanthryl group;
- R3 is a hydrogen atom;
- R5 is a hydrogen atom;
- R6 is a hydrogen atom or a halogen atom;
- R7 is a hydrogen atom or a halogen atom;
- R8 is a hydrogen atom;
- R2′ is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, an substituted or unsubstituted anthracyl group, a substituted or unsubstituted styryl group or a substituted or unsubstituted phenanthryl group;
- R3′ is a hydrogen atom;
- R5′ is a hydrogen atom;
- R6′ is a hydrogen atom or a halogen atom;
- R7′ is a hydrogen atom or a halogen atom;
- and
- R8′ is a hydrogen atom,
- and pharmaceutically acceptable salts thereof.
A method of inhibiting immunostimulation in a subject, the method comprising administering an effective amount of a substituted bis-9-aminoacridine composition to said subject, the bis-9-aminoacridine composition comprising a compound having the structural formula E
- wherein
- RB on the first 9-aminoacridine is covalently attached to RB′ on the second 9-aminoacridine by linker group Y, wherein the linker group Y is an alkyl group, an ester group, an alkoxyalkyl group, an alkylamino group, an dialkylamino group, an amido group, a cyclohexane, a cyclohexanedieyl, a piperazino group, 1-4, piperazinedieyl, or any combination thereof;
- OR2 is a lower alkyl group;
- OR2′ is a lower alkyl group;
- R3 is a hydrogen atom or a lower alkoxy group;
- R3′ is a hydrogen atom or a lower alkoxy group;
- X is a halogen atom;
- X′ is a halogen atom,
- and pharmaceutically acceptable salts thereof.
A method of inhibiting immunostimulation in a subject, the method comprising administering an effective amount of a composition to said subject, the composition comprising a compound having the structural formula F
- wherein
- RB is covalently linked to RB′ by linker Y, wherein the linker group Y is an alkyl group, an ester group, an alkoxyalkyl group, an alkylamino group, an dialkylamino group, an amido group, a cyclohexane, a cyclohexanedieyl, a piperazino group, 1-4, piperazinedieyl, or any combination thereof;
- R2 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, an substituted or unsubstituted anthracyl group, a substituted or unsubstituted styryl group or a substituted or unsubstituted phenanthryl group;
- R3 is a hydrogen atom;
- R5 is a hydrogen atom;
- R6 is a hydrogen atom or a halogen atom;
- R7 is a hydrogen atom or a halogen atom;
- R8 is a hydrogen atom;
- RB′ is linked covalently to RB by linker Y;
- OR2′ is a lower alkyl group;
- and
- R3′ is a hydrogen atom, or a lower alkoxy group;
- X is a halogen atom,
- and pharmaceutically acceptable salts thereof.
A substituted 4-quinolinamine composition having the structural formula A
- wherein
- RA is hydrogen atom or a lower alkyl group;
- RB is a substituted or unsubstituted alkyl, alkenyl or alkynyl secondary or tertiary amine;
- R2 is a substituted naphthyl group, an substituted or unsubstituted anthracyl group, a substituted or unsubstituted phenanthryl group or a substituted or unsubstituted styryl group;
- R3 is a hydrogen atom;
- R5 is a hydrogen atom;
- R6 is a hydrogen atom or a halogen atom;
- R7 is a hydrogen atom or a halogen atom;
- and
- R8 is a hydrogen atom,
- and pharmaceutically acceptable salts thereof.
A substituted 4-quinolinamine composition having the structural formula B
- wherein
- the phenyl group can be substituted at R9, R10, R11, R12 and R13, wherein said substituted phenyl group comprises one or more substitutions selected from the group consisting of an alkyl group, an alkoxy group, an alkoxyalkyl group, an alkylaminoalkyl group, an ester group, an alkylamino group, an dialkylamino group, a cyclic amino group, a furan group, a thiophene group, a halogen atom or any combination thereof;
- R2 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted anthracyl group, a substituted or unsubstituted styryl group or a substituted or unsubstituted phenanthryl group;
- R3 is a hydrogen atom;
- R5 is a hydrogen atom;
- R6 is a hydrogen atom or a halogen atom;
- R7 is a hydrogen atom, a halogen atom or an alkyl halogen atom;
- R8 is a hydrogen atom,
- and pharmaceutically acceptable salts thereof.
A substituted 4-quinolinamine composition having the structural formula C
- wherein
- the phenyl group can be unsubstituted or substituted at R9, R10, R11, R12 and R13, wherein said substituted phenyl group comprises one or more substitutions selected from the group consisting of an alkyl group, an alkoxy group, an alkoxyalkyl group, an alkylaminoalkyl group, an ester group, an alkylamino group, an dialkylamino group, a cyclic amino group, a furan group, a thiophene group, a halogen atom, or any combination thereof;
- n is 0 to 4 CH2;
- R2 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted anthracyl group, a substituted or unsubstituted styryl group or a substituted or unsubstituted phenanthryl group;
- R3 is a hydrogen atom;
- R5 is a hydrogen atom;
- R6 is a hydrogen atom or a halogen atom;
- R7 is a hydrogen atom, a halogen atom or an alkyl halogen atom;
- R8 is a hydrogen atom,
- and pharmaceutically acceptable salts thereof.
A substituted bis-4-quinolinamine composition having the structural formula D
- wherein
- RB on the first 4-quinolinamine is covalently attached to RB′ on the second 4-quinolinamine by linker group Y, wherein the linker group Y is an alkyl group, an ester group, an alkoxyalkyl group, an alkylamino group, an dialkylamino group, an amido group, a cyclohexane, a cyclohexanedieyl, a piperazino group, 1-4, piperazinedieyl, or any combination thereof;
- R2 is a substituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted anthracyl group, a substituted or unsubstituted styryl group or a substituted or unsubstituted phenanthryl group;
- R3 is a hydrogen atom;
- R5 is a hydrogen atom;
- R6 is a hydrogen atom or a halogen atom;
- R7 is a hydrogen atom or a halogen atom;
- R8 is a hydrogen atom;
- R2′ is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, an substituted or unsubstituted anthracyl group, a substituted or unsubstituted styryl group or a substituted or unsubstituted phenanthryl group;
- R3′ is a hydrogen atom;
- R5′ is a hydrogen atom;
- R6′ is a hydrogen atom or a halogen atom;
- R7′ is a hydrogen atom or a halogen atom;
- and
- R8′ is a hydrogen atom,
- and pharmaceutically acceptable salts thereof.
A substituted bis-9-aminoacridine composition having the structural formula E
- wherein
- RB on the first 9-aminoacridine is covalently attached to RB′ on the second 9-aminoacridine by linker group Y, wherein the linker group Y is an alkyl group, an ester group, an alkoxyalkyl group, an alkylamino group, an dialkylamino group, an amido group, a cyclohexane, a cyclohexanedieyl, a piperazino group, 1-4, piperazinedieyl, or any combination thereof;
- OR2 is a lower alkyl group;
- OR2′ is a lower alkyl group;
- R3 is a lower alkoxy group;
- R3′ is a lower alkoxy group;
- X is a halogen atom;
- X′ is a halogen atom,
- and pharmaceutically acceptable salts thereof.
A 4-quinolinamine, 9-aminoacridine composition having the structural formula F
- wherein
- RB is covalently linked to RB′ by linker Y, wherein the linker group Y is an alkyl group, an ester group, an alkoxyalkyl group, an alkylamino group, an dialkylamino group, an amido group, a cyclohexane, a cyclohexanedieyl, a piperazino group, 1-4, piperazinedieyl, or any combination thereof;
- R2 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, an substituted or unsubstituted anthracyl group, a substituted or unsubstituted styryl group or a substituted or unsubstituted phenanthryl group;
- R3 is a hydrogen atom;
- R5 is a hydrogen atom;
- R6 is a hydrogen atom or a halogen atom;
- R7 is a hydrogen atom or a halogen atom;
- R8 is a hydrogen atom;
- RB′ is linked covalently to RB by linker Y;
- OR2′ is a lower alkyl group;
- and
- R3′ is a hydrogen atom, or a lower alkoxy group;
- X is a halogen atom,
- and pharmaceutically acceptable salts thereof.
Dependencies are inferred from the claim text.