US 2004/0006242 A1Published application

Immunomodulatory compounds and method of use thereof

OwnerLynn D. Hawkins, Sally T. Ishizakainventors

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Abstract

The present invention is directed to methods of treating diseases and disorders related to immune responses by administering one or more immunomodulatory compounds. In particular, the invention is directed to methods of stimulating and reducing immune responses, treating autoimmune conditions, treating allergic reactions and asthma, and preventing ischemic damage and asthma by administering one or more immunomodulatory compounds.

Claims17

Dependent claims

A method of inducing or stimulating an immune response in a subject comprising administering an effective amount of a compound of the formula I, II, or III, as the active ingredient:

291
Wherein for each of formula I, II, or III:
R1 is selected from the group consisting of
(a) C(O);
(b) C(O)—C1-14 alkyl-C(O), wherein said C1-14 alkyl is optionally substituted with hydroxy, C1-5 alkoxy, C1-5 alkylenedioxy, C1-5 alkylamino, or C1-5-alkyl-aryl, wherein said aryl moiety of said C1-15-alkyl-aryl is optionally substituted with C1-5 alkoxy, C1-5 alkyl amino, C1-5 alkoxy-amino, C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C(O)—C1-5 alkyl C(O)OH, —O—C-1-5 alkylamino-C(O)—C1-5 alkyl-C(O)—C1-5 alkyl;
(c) C2 to C15 straight or branched chain alkyl optionally substituted with hydroxy or alkoxy;
and
(d) —C(O)—C6-12 arylene-C(O)— wherein said arylene is optionally substituted with hydroxy, halogen, nitro or armno;
a and b are independently 0, 1, 2, 3 or 4;
d, d′, d″, e, e′ and e″ are independently an integer from 1 to 4;
X1, X2, Y1 and Y2 are independently selected from the group consisting of null, oxygen, NH and N(C(O)C1-4 alkyl), and N(C1-4 alkyl)2;
W1 and W2 are independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R2 and R5 are independently selected from the group consisting of:
(a) C2 to C20 straight chain or branched chain alkyl which is optionally substituted with oxo, hydroxy or alkoxy,
(b) C2 to C20 straight chain or branched chain alkenyl or dialkenyl which is optionally substituted with oxo, hydroxy or alkoxy;
(c) C2 to C20 straight chain or branched chain alkoxy which is optionally substituted with oxo, hydroxy or alkoxy;
(d) —NH—C2 to C20 straight chain or branched chain alkyl, wherein said alkyl group is optionally substituted with oxo, hydroxy or alkoxy;
and
(e)
292
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R1 and R6 are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl or alkenyl optionally substituted with oxo or fluoro;
R4 and R7 are independently selected from the group consisting of C(O)C2 to C20 straight chain or branched chain alkyl or alkenyl;
C2 to C20 straight chain or branched chain alkyl;
C2 to C20 straight chain or branched chain alkoxy;
C2 to C20 straight chain or branched chain alkenyl;
wherein said alkyl, alkenyl or alkoxy groups can be independently and optionally substituted with hydroxy, fluoro or C1 to C5 alkoxy;
G1, G2, G3 and G4 are independently selected from the group consisting of oxygen, methylene, amino, thiol, —NHC(O)—, and —N(C(O)C1-4 alkyl)—;
or G2R4 or G4R7 may together be a hydrogen atom or hydroxyl;
or a pharmaceutically acceptable salt thereof;
and wherein for Formula II:
a′ and b′ are independently 2, 3, 4, 5, 6, 7, or 8, preferably 2;
Z1 is selected from the group consisting of —OP(O)(OH)2, —P(O)(OH)2,—OP(O)(OR8)(OH) where R8is a C1-C4 alkyl chain, —OS(O)2OH,—S(O)2OH—,—CO2H, —OB(OH)2, —OH, —CH3, —NH2, NR93 where R9 is a C1-C4 alkyl chain;
Z2 is —OP(O)(OH)2, —P(O)(OH)2′, —OP(O)(OR10)(OH) where R10 is a C1-C4 alkyl chain, —OS (O)2OH,—S(O)2OH, CO2H, —OB(OH)2, —OH, CH3, —NH2, —NR11, where R11 is a C1-C4 alkyl chain;
and wherein for Formula 3:
R12 is selected from H and a C1-C4 alkyl chain;
or a pharmaceutical salt thereof,
with the proviso that the compounds of formula I, II, or III are not
293

36 more elements

A method for upregulation of the immune system comprising administering a therapeutically effective amount of a compound of formula I, II, or III,

294
Wherein for each of formula I, II, or III:
R1 is selected from the group consisting of
(a) C(O);
(b) C(O)—C1-14 alkyl-C(O), wherein said C1-14 alkyl is optionally substituted with hydroxy, C1-5 alkoxy, C1-5 alkylenedioxy, C1-5 alkylamino, or C1-5-alkyl-aryl, wherein said aryl moiety of said C1-15-alkyl-aryl is optionally substituted with C1-5 alkoxy, C1-5 alkyl amino, C1-5 alkoxy-amino, C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C(O)—C1-5 alkyl C(O)OH, —O—C1-5 alkylamino-C(O)—C1-5 alkyl-C(O)—C1-5 alkyl;
(c) C2 to C15 straight or branched chain alkyl optionally substituted with hydroxy or alkoxy;
and
(d) —C(O)—C6-12 arylene-C(O)— wherein said arylene is optionally substituted with hydroxy, halogen, nitro or amino;
a and b are independently 0, 1, 2, 3 or 4;
d, d′, d″, e, e′ and e″ are independently an integer from 1 to 4;
X1, X2, Y1 and Y2 are independently selected from the group consisting of null, oxygen, NH and N(C(O)C1-4 alkyl), and N(C1-4 alkyl)2;
W1 and W2 are independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R2 and R5 are independently selected from the group consisting of:
(a) C2 to C20 straight chain or branched chain alkyl which is optionally substituted with oxo, hydroxy or alkoxy,
(b) C2 to C20 straight chain or branched chain alkenyl or dialkenyl which is optionally substituted with oxo, hydroxy or alkoxy;
(c) C2 to C20 straight chain or branched chain alkoxy which is optionally substituted with oxo, hydroxy or alkoxy;
(d) —NH—C2 to C20 straight chain or branched chain alkyl, wherein said alkyl group is optionally substituted with oxo, hydroxy or alkoxy;
and
(e)
295
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R1 and R6 are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl or alkenyl optionally substituted with oxo or fluoro;
R4 and R7 are independently selected from the group consisting of C(O)C2 to C20 straight chain or branched chain alkyl or alkenyl;
C2 to C20 straight chain or branched chain alkyl;
C2 to C20 straight chain or branched chain alkoxy;
C2 to C20 straight chain or branched chain alkenyl;
wherein said alkyl, alkenyl or alkoxy groups can be independently and optionally substituted with hydroxy, fluoro or C, to C5 alkoxy;
G1, G2, G3 and G4 are independently selected from the group consisting of oxygen, methylene, amino, thiol, —NHC(O)—, and —N(C(O)C1-4 alkyl)—;
or G2R4 or G4R7 may together be a hydrogen atom or hydroxyl;
or a pharmaceutically acceptable salt thereof;
and wherein for Formula II:
a′ and b′ are independently 2, 3, 4, 5, 6, 7, or 8, preferably 2;
Z1 is selected from the group consisting of —OP(O)(OH)2,—P(O)(OH)2,—OP(O)(OR8)(OH) where R8 is a C1-C4 alkyl chain, —OS(O)2OH,—S(O)2OH—,—CO2H, —OB(OH)2, —OH, —CH3, —NH2, NR93 where R9 is a C1-C4 alkyl chain;
Z2 is —OP(O)(OH)2, —P(O)(OH)2′, —OP(O)(OR10) (OH) where R10is a C1-C4 alkyl chain, —OS (O)2OH,—S(O)2OH, CO2H, —OB(OH)2, —OH, CH3, —NH2, —NR11, where R11 is a C1-C4 alkyl chain;
and wherein for Formula 3:
R12 is selected from H and a C1-C4 alkyl chain;
or a pharmaceutical salt thereof,
with the proviso that the compounds of formula I, II, or III are not
296
wherein said compound has immunostimulatory activity.

37 more elements

A method of reducing an immune response in a subject, the method comprising administering to the subject a compound of formula I, II, or III

297
Wherein for each of formula I, IT, or III:
R1 is selected from the group consisting of
(a) C(O);
(b) C(O)—C1-14 alkyl-C(O), wherein said C1-14 alkyl is optionally substituted with hydroxy, C1-5 alkoxy, C1-5 alkylenedioxy, C1-5alkylamino, or C1-5-alkyl-aryl, wherein said aryl moiety of said C1-15-alkyl-aryl is optionally substituted with C1-5 alkoxy, C1-5 alkyl amino, C1-5 alkoxy-amino, C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C5 alkoxy, —O—C1-5 alkylamino-C (O)—C1-5 alkyl C(O)OH, —O—C1-5 alkylamino-C(O)—C1-5 alkyl-C(O)—C1-5 alkyl;
(c) C2 to C15 straight or branched chain alkyl optionally substituted with hydroxy or alkoxy;
and
(d) —C(O)—C6-12 arylene-C(O)— wherein said arylene is optionally substituted with hydroxy, halogen, nitro or amino;
a and b are independently 0, 1, 2, 3 or 4;
d, d′, d″, e, e′ and e″ are independently an integer from 1 to 4;
X1, X2, Y1 and Y2 are independently selected from the group consisting of null, oxygen, NH and N(C(O)C1-4 alkyl), and N(C1-4 alkyl)2;
W1 and W2 are independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R2 and R5 are independently selected from the group consisting of:
(a) C2 to C20 straight chain or branched chain alkyl which is optionally substituted with oxo, hydroxy or alkoxy,
(b) C2 to C20 straight chain or branched chain alkenyl or dialkenyl which is optionally substituted with oxo, hydroxy or alkoxy;
(c) C2 to C20 straight chain or branched chain alkoxy which is optionally substituted with oxo, hydroxy or alkoxy;
(d) —NH—C2 to C20 straight chain or branched chain alkyl, wherein said alkyl group is optionally substituted with oxo, hydroxy or alkoxy;
and
(e)
298
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R1 and R6 are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl or alkenyl optionally substituted with oxo or fluoro;
R4 and R7 are independently selected from the group consisting of C(O)C2 to C20 straight chain or branched chain alkyl or alkenyl;
C2 to C20 straight chain or branched chain alkyl;
C2 to C20 straight chain or branched chain alkoxy;
C2 to C20 straight chain or branched chain alkenyl;
wherein said alkyl, alkenyl or alkoxy groups can be independently and optionally substituted with hydroxy, fluoro or C1 to C5 alkoxy;
G1, G2, G3 and G4 are independently selected from the group consisting of oxygen, methylene, amino, thiol, —NHC(O)—, and —N(C(O)C1-4 alkyl)-;
or G2R4 or G4R7 may together be a hydrogen atom or hydroxyl;
or a pharmaceutically acceptable salt thereof;
and wherein for Formula II:
a′ and b′ are independently 2, 3, 4, 5, 6, 7, or 8, preferably 2;
Z1 is selected from the group consisting of —OP(O)(OH)2,—P(O)(OH)2,—OP(O)(OR8)(OH) where R8 is a C1-C4 alkyl chain, —OS(O)2OH,—S(O)2OH—,—CO2H, —OB(OH)2, —OH, —CH3, —NH2, NR93 where R9 is a C1-C4 alkyl chain;
Z2 is —OP(O)(OH)2, —P(O)(OH)2′, —OP(O)(OR10)(OH) where R10is a C1-C4 alkyl chain, —OS (O)2OH,—S(O)2OH, CO2H, —OB(OH)2, —OH, CH3, —NH2, —NR11, where R11 is a C1-C4 alkyl chain;
and wherein for Formula 3:
R12 is selected from H and a C1-C4 alkyl chain;
or a pharmaceutical salt thereof,
with the proviso that the compounds of formula I, II, or III are not
299
in an amount sufficient to reduce an immune response in the subject and thereby induce a therapeutic effect.

37 more elements

A method of desensitizing a subject against the occurrence of an allergic reaction in response to contact with a particular antigen or allergen, comprising administering to the subject an effective amount of an immunostimulatory compound of the formula I, II, or III

300
Wherein for each of formula I, II, or III:
R1 is selected from the group consisting of
(a) C(O);
(b) C(O)—C1-14 alkyl-C(O), wherein said C1-14 alkyl is optionally substituted with hydroxy, C1-5 alkoxy, C1-5 alkylenedioxy, C1-5 alkylamino, or C 1-5-alkyl-aryl, wherein said aryl moiety of said C1-15-alkyl-aryl is optionally substituted with C1-5 alkoxy, C1-5 alkyl amino, C1-5 alkoxy-amino, C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C(O)—C1-5 alkyl C(O)OH, —O—C1-5 alkylamino-C(O)—C1-5 alkyl-C(O)—C1-5 alkyl;
(c) C2 to C15 straight or branched chain alkyl optionally substituted with hydroxy or alkoxy;
and
(d) —C(O)—C6-12 arylene-C(O)— wherein said arylene is optionally substituted with hydroxy, halogen, nitro or amino;
a and b are independently 0, 1, 2, 3 or 4;
d, d′, d″, e, e′ and e″ are independently an integer from 1 to 4;
X1, X2, Y1 and Y2 are independently selected from the group consisting of null, oxygen, NH and N(C(O)C1-4 alkyl), and N(C1-4 alkyl)2;
W1 and W2 are independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R2 and R5 are independently selected from the group consisting of:
(a) C2 to C20 straight chain or branched chain alkyl which is optionally substituted with oxo, hydroxy or alkoxy,
(b) C2 to C20 straight chain or. branched chain alkenyl or dialkenyl which is optionally substituted with oxo, hydroxy or alkoxy;
(c) C2 to C20 straight chain or branched chain alkoxy which is optionally substituted with oxo, hydroxy or alkoxy;
(d) —NH—C2 to C20 straight chain or branched chain alkyl, wherein said alkyl group is optionally substituted with oxo, hydroxy or alkoxy;
and
(e)
301
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R1 and R6 are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl or alkenyl optionally substituted with oxo or fluoro;
R4 and R7 are independently selected from the group consisting of C(O)C2 to C20 straight chain or branched chain alkyl or alkenyl;
C2 to C20 straight chain or branched chain alkyl;
C2 to C20 straight chain or branched chain alkoxy;
C2 to C20 straight chain or branched chain alkenyl;
wherein said alkyl, alkenyl or alkoxy groups can be independently and optionally substituted with hydroxy, fluoro or C1 to C5 alkoxy;
G1, G2, G3 and G4 are independently selected from the group consisting of oxygen, methylene, amino, thiol, —NHC(O)—, and —N(C(O)C1-4alkyl)—;
or G2R4 or G4R7 may together be a hydrogen atom or hydroxyl;
or a pharmaceutically acceptable salt thereof;
and wherein for Formula II:
a′ and b′ are independently 2, 3, 4, 5, 6, 7, or 8, preferably 2;
Z1 is selected from the group consisting of —OP(O)(OH2,—P(O)(OH)2,—OP(O)(OR8)(OH) where R8 is a C1-C4 alkyl chain, —OS(O)2OH,—S(O)2OH—,—CO2H, —OB(OH)2, —OH, —CH3, —NH2, NR93 where R9 is a C1-C4 alkyl chain;
Z2 is —OP(O)(OH)2, —P(O)(OH)2′, —OP(O)(OR10)(OH) where R10is a C1-C4 alkyl chain, —OS(O)2OH,—S(O)2OH, CO2H, —OB(OH)2, —OH, CH3, —NH2, —NR11, where R11 is a C1-C4 alkyl chain;
and wherein for Formula 3:
R12 is selected from H and a C1-C4 alkyl chain;
or a pharmaceutical salt thereof,
with the proviso that the compounds of formula I, II, or III are not
302
as the active ingredient.

37 more elements

A method of treating an autoimmune disease, the method comprising administering to a subject diagnosed as having an autoimmune disease a pharmaceutical composition comprising (a) a compound of formula I, II, or III,

303
Wherein for each of formula I, II, or III:
R1 is selected from the group consisting of
(a) C(O);
(b) C(O)—C1-14 alkyl-C(O), wherein said C1-14 alkyl is optionally substituted with hydroxy, C1-5 alkoxy, C1-5 alkylenedioxy, C1-5 alkylamino, or C1-5-alkyl-aryl, wherein said aryl moiety of said C1-15-alkyl-aryl is optionally substituted with C1-5 alkoxy, C1-5 alkyl amino, C1-5 alkoxy-amino, C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C(O)—C1-5 alkyl C(O)OH, —O—C1-5 alkylamino-C(O)—C1-5 alkyl-C(O)—C1-5 alkyl;
(c) C2 to C15 straight or branched chain alkyl optionally substituted with hydroxy or alkoxy;
and
(d) —C(O)—C6-12 arylene-C(O)— wherein said arylene is optionally substituted with hydroxy, halogen, nitro or amino;
a and b are independently 0, 1, 2, 3 or 4;
d, d′, d″, e, e′ and e″ are independently an integer from 1 to 4;
X1, X2, Y1 and Y2 are independently selected from the group consisting of null, oxygen, NH and N(C(O)C1-4 alkyl), and N(C1-4 alkyl)2;
W1 and W2 are independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R2 and R5 are independently selected from the group consisting of:
(a) C2 to C20 straight chain or branched chain alkyl which is optionally substituted with oxo, hydroxy or alkoxy,
(b) C2 to C20 straight chain or branched chain alkenyl or dialkenyl which is optionally substituted with oxo, hydroxy or alkoxy;
(c) C2 to C20 straight chain or branched chain alkoxy which is optionally substituted with oxo, hydroxy or alkoxy;
(d) —NH—C2 to C20 straight chain or branched chain alkyl, wherein said alkyl group is optionally substituted with oxo, hydroxy or alkoxy;
and
(e)
304
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R1 and R6 are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl or alkenyl optionally substituted with oxo or fluoro;
R4 and R7 are independently selected from the group consisting of C(O)C2 to C20 straight chain or branched chain alkyl or alkenyl;
C2 to C20 straight chain or branched chain alkyl;
C2 to C20 straight chain or branched chain alkoxy;
C2 to C20 straight chain or branched chain alkenyl;
wherein said alkyl, alkenyl or alkoxy groups can be independently and optionally substituted with hydroxy, fluoro or C1 to C5 alkoxy;
G1, G2, G3 and G4 are independently selected from the group consisting of oxygen, nethylene, amino, thiol, —NHC(O)—, and —N(C(O)C1-4 alkyl)—;
or G2R4 or G4R7 may together be a hydrogen atom or hydroxyl;
or a pharmaceutically acceptable salt thereof;
and wherein for Formula II:
a′ and b′ are independently 2, 3, 4, 5, 6, 7, or 8, preferably 2;
Z1 is selected from the group consisting of —OP(O)(OH)2,—P(O)(OH)2,—OP(O)(OR8)(OH) where R8 is a C1-C4 alkyl chain, —OS(O)2OH,—S(O)2OH—,—CO2H, —OB(OH)2, —OH, —CH3, —NH2, NR93 where R9 is a C1-C4 alkyl chain;
Z2 is —OP(O)(OH)2, —P(O)(OH)2′, —OP(O)(OR10)(OH) where R10is a C1-C4 alkyl chain, —OS(O)2OH,—S(O)2OH, CO2H,—OB(OH)2, —OH, CH3, —NH2, —NR11, where R11 is a C1-C4 alkyl chain;
and wherein for Formula 3:
R12 is selected from H and a C1-C4 alkyl chain;
or a pharmaceutical salt thereof,
with the proviso that the compounds of formula I, II, or III are not
305
or a salt thereof, and (b) a pharmaceutically acceptable carrier therefor, wherein the compound is an immunoinhibitory compound.

37 more elements

A method of treating an inflammmatory condition in a subject comprising administering to the subject an effective amount of a compound of the formula I, II, or III

306
Wherein for each of formula I, II, or III:
R1 is selected from the group consisting of
(a) C(O);
(b) C(O)—C1-14 alkyl-C(O), wherein said C1-14 alkyl is optionally substituted with hydroxy, C1-5 alkoxy, C1-5 alkylenedioxy, C1-5 alkylamino, or C1-5-alkyl-aryl, wherein said aryl moiety of said C1-15-alkyl-aryl is optionally substituted with C1-5 alkoxy, C1-5 alkyl amino, C1-5 alkoxy-amino, C1-5 alkylamino-C1-5 alkoxy, —O-C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C (O)—C1-5 alkyl C(O)OH, —O—C1-5 alkylamino-C(O)—C1-5 alkyl-C(O)—C1-5 alkyl;
(c) C2 to C15 straight or branched chain alkyl optionally substituted with hydroxy or alkoxy;
and
(d) —C(O)—C6-12 arylene-C(O)— wherein said arylene is optionally substituted with hydroxy, halogen, nitro or amino;
a and b are independently 0, 1, 2, 3 or 4;
d, d′, d″, e, e′ and e″ are independently an integer from 1 to 4;
X1, X2, Y1 and Y2 are independently selected from the group consisting of null, oxygen, NH and N(C(O)C1-4 alkyl), and N(C1-4 alkyl)2;
W1 and W2 are independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R2 and R5 are independently selected from the group consisting of:
(a) C2 to C20 straight chain or branched chain alkyl which is optionally substituted with oxo, hydroxy or alkoxy,
(b) C2 to C20 straight chain or branched chain alkenyl or dialkenyl which is optionally substituted with oxo, hydroxy or alkoxy;
(c) C2 to C20 straight chain or branched chain alkoxy which is optionally substituted with oxo, hydroxy or alkoxy;
(d) —NH—C2 to C20 straight chain or branched chain alkyl, wherein said alkyl group is optionally substituted with oxo, hydroxy or alkoxy;
and
(e)
307
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R1 and R6 are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl or alkenyl optionally substituted with oxo or fluoro;
R4 and R7 are independently selected from the group consisting of C(O)C2 to C20 straight chain or branched chain alkyl or alkenyl;
C2 to C20 straight chain or branched chain alkyl;
C2 to C20 straight chain or branched chain alkoxy;
C2 to C20 straight chain or branched chain alkenyl;
wherein said alkyl, alkenyl or alkoxy groups can be independently and optionally substituted with hydroxy, fluoro or C1 to C5 alkoxy;
G1, G2, G3 and G4 are independently selected from the group consisting of oxygen, methylene, amino, thiol, —NHC(O)—, and —N(C(O)C1-4 alkyl)—;
or G2R4 or G4R7 may together be a hydrogen atom or hydroxyl;
or a pharmaceutically acceptable salt thereof;
and wherein for Formula II:
a′ and b′ are independently 2, 3, 4, 5, 6, 7, or 8, preferably 2;
Z1 is selected from the group consisting of —OP(O)(OH)2,—P(O)(OH)2,—OP(O)(OR8)(OH) where R8is a C1-C4 alkyl chain, —OS(O)2OH,—S(O)2OH—,—CO2H, —OB(OH)2, —OH, —CH3, —NH2, NR93 where R9 is a C1-C4 alkyl chain;
Z2 is —OP(O)(OH)2, —P(O)(OH)2′, —OP(O)(OR10)(OH) where R10is a C1-C4 alkyl chain, —OS(O)2OH,—S(O)2OH, CO2H, —OB(OH)2, —OH, CH3, —NH2, —NR11, where, R11 is a C1-C4 alkyl chain;
and wherein for Formula 3:
R12 is selected from H and a C1-C4 alkyl chain;
or a pharmaceutical salt thereof,
with the proviso that the compounds of formula I, II, or III are not
308
as the active ingredient.

37 more elements

An immunostimulatory remedy containing, as the active ingredient, a compound of the formula I, II, or III:

309
Wherein for each of formula I, II, or III:
R1 is selected from the group consisting of
(a) C(O);
(b) C(O)—C1-4 alkyl-C(O), wherein said C1-4 alkyl is optionally substituted with hydroxy, C1-5 alkoxy, C1-5 alkylenedioxy, C1-5 alkylamino, or C1-5-alkyl-aryl, wherein said aryl moiety of said C1-15-alkyl-aryl is optionally substituted with C1-5 alkoxy, C1-5 alkyl amino, C1-5 alkoxy-amino, C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C(O)—C1-5 alkyl C(O)OH, —O—C1-5 alkylamino-C(O)—C1-5 alkyl-C(O)—C1-5 alkyl;
(c) C2 to C15 straight or branched chain alkyl optionally substituted with hydroxy or alkoxy;
and
(d) —C(O)—C6-12 arylene-C(O)— wherein said arylene is optionally substituted with hydroxy, halogen, nitro or amino;
a and b are independently 0, 1, 2, 3 or 4;
d, d′, d″, e, e′ and e″ are independently an integer from 1 to 4;
X1, X2, Y1 and Y2 are independently selected from the group consisting of null, oxygen, NH and N(C(O)C1-4 alkyl), and N(C1-4 alkyl)2;
W1 and W2 are independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R2 and R5 are independently selected from the group consisting of:
(a) C2 to C20 straight chain or branched chain alkyl which is optionally substituted with oxo, hydroxy or alkoxy,
(b) C2 to C20 straight chain or branched chain alkenyl or dialkenyl which is optionally substituted with oxo, hydroxy or alkoxy;
(c) C2 to C20 straight chain or branched chain alkoxy which is optionally substituted with oxo, hydroxy or alkoxy;
(d) —NH—C2 to C20 straight chain or branched chain alkyl, wherein said alkyl group is optionally substituted with oxo, hydroxy or alkoxy;
and
(e)
310
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R1 and R6 are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl or alkenyl optionally substituted with oxo or fluoro;
R4 and R7 are independently selected from the group consisting of C(O)C2 to C20 straight chain or branched chain alkyl or alkenyl;
C2 to C20 straight chain or branched chain alkyl;
C2 to C20 straight chain or branched chain alkoxy;
C2 to C20 straight chain or branched chain alkenyl;
wherein said alkyl, alkenyl or alkoxy groups can be independently and optionally substituted with hydroxy, fluoro or C1 to C5 alkoxy;
G1, G2, G3 and G4 are independently selected from the group consisting of oxygen, methylene, amino, thiol, —NHC(O)—, and —N(C(O)C1-4 alkyl)—;
or G2R4 or G4R7 may together be a hydrogen atom or hydroxyl;
or a pharmaceutically acceptable salt thereof;
and wherein for Formula II:
a′ and b′ are independently 2, 3, 4, 5, 6, 7, or 8, preferably 2;
Z1 is selected from the group consisting of —OP(O)(OH)2,—P(O)(OH)2,—OP(O)(OR8)(OH) where R8 is a C1-C4 alkyl chain, —OS(O)2OH,—S(O)2OH—,—CO2H, —OB(OH)2, —OH, —CH3, —NH2, NR93 where R9 is a C1-C4 alkyl chain;
Z2 is —OP(O)(OH)2, —P(O)(OH)2′, ′OP(O)(OR10)(OH) where R10 is a C1-C4 alkyl chain, —OS (O)2OH,—S(O)2OH, CO2H, —OB(OH)2, —OH, CH3, —NH2, —NR11, where R11 is a C1-C4 alkyl chain;
and wherein for Formula 3:
R2 is selected from H and a C1-C4 alkyl chain;
or a pharmaceutical salt thereof,
with the proviso that the compounds of formula I, II, or III are not
311

36 more elements

A method of preventing, ameliorating, or delaying asthma in a subject, the method comprising administering to the subject an effective amount of a compound of the formula I, II, or III

312
Wherein for each of formula I, II, or III:
R1 is selected from the group consisting of
(a) C(O);
(b) C(O)—C1-14 alkyl-C(O), wherein said C1-14 alkyl is optionally substituted with hydroxy, C1-5 alkoxy, C1-5 alkylenedioxy, C1-5 alkylamino, or C1-5-alkyl-aryl, wherein said aryl moiety of said C1-15-alkyl-aryl is optionally substituted with C1-5 alkoxy, C1-5 alkyl amino, C1-5 alkoxy-amino, C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C(O)—C1-5 alkyl C(O)OH, —O—C1-5 alkylamino-C(O)—C1-5 alkyl-C(O)—C1-5 alkyl;
(c) C2 to C15 straight or branched chain alkyl optionally substituted with hydroxy or alkoxy;
and
(d) —C(O)—C6-12 arylene-C(O)— wherein said arylene is optionally substituted with hydroxy, halogen, nitro or amino;
a and b are independently 0, 1, 2, 3 or 4;
d, d′, d″, e, e′ and e″ are independently an integer from 1 to 4;
X1, X2, Y1 and Y2 are independently selected from the group consisting of null, oxygen, NH and N(C(O)C1-4 alkyl), and N(C1-4 alkyl)2;
W1 and W2 are independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R2 and R5 are independently selected from the group consisting of:
(a) C2 to C20 straight chain or branched chain alkyl which is optionally substituted with oxo, hydroxy or alkoxy,
(b) C2 to C20 straight chain or branched chain alkenyl ordialkenyl which is optionally substituted with oxo, hydroxy or alkoxy;
(c) C2 to C20 straight chain or branched chain alkoxy which is optionally substituted with oxo, hydroxy or alkoxy;
(d) —NH—C2 to C20 straight chain or branched chain alkyl, wherein said alkyl group is optionally substituted with oxo, hydroxy or alkoxy;
and
(e)
313
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R1 and R6 are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl or alkenyl optionally substituted with oxo or fluoro;
R4 and R7 are independently selected from the group consisting of C(O)C2 to C20 straight chain or branched chain alkyl or alkenyl;
C2 to C20 straight chain or branched chain alkyl;
C2 to C20 straight chain or branched chain alkoxy;
C2 to C20 straight chain or branched chain alkenyl;
wherein said alkyl, alkenyl or alkoxy groups can be independently and optionally substituted with hydroxy, fluoro or C1 to C5 alkoxy;
G1, G2, G3 and G4 are independently selected from the group consisting of oxygen, methylene, amino, thiol, —NHC(O)—, and —N(C(O)C1-4 alkyl)—;
or G2R4 or G4R7 may together be a hydrogen atom or hydroxyl;
or a pharmaceutically acceptable salt thereof;
and wherein for Formula II:
a′ and b′ are independently 2, 3, 4, 5, 6, 7, or 8, preferably 2;
Z1 is selected from the group consisting of —OP(O)(OH)2,—P(O)(OH)2,—OP(O)(OR8)(OH) where R8 is a C1-C4 alkyl chain, —OS(O)2OH,—S(O)2OH—,—CO2H, —OB(OH)2, —OH, —CH3, —NH2, NR93 where R9 is a C1-C4 alkyl chain;
Z2 is —OP(O)(OH)2, —P(O)(OH)2′, —OP(O)(OR10)(OH) where R10is a C1-C4 alkyl chain, —OS(O)2OH,—S(O)2OH, CO2H, —OB(OH)2, —OH, CH3, —NH2, —NR11, where R11 is a C1-C4 alkyl chain;
and wherein for Formula 3:
R12 is selected from H and a C1-C4 alkyl chain;
or a pharmaceutical salt thereof,
with the proviso that the compounds of formula I, II, or III are not
314
as the active ingredient.

37 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/157,791Filed 28 May 2002
Priority: 1 Feb 1999
Published: 8 Jan 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification35 codes

A61K 39/39
Medicinal preparations containing antigens or antibodies: characterised by the immunostimulating additives, e.g. chemical adjuvants
A61K 31/16
Medicinal preparations containing organic active ingredients: amides, e.g. hydroxamic acids
A61K 31/17
Amides, e.g. hydroxamic acids: having the group >N—C—N< or >N—C—N<, e.g. urea, thiourea, carmustine
A61K 31/6615
Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos: compounds having two or more…

Family

Application60/118,131Us provisional application · filed 1 Feb 1999
Application09/496,152Continuation in part · filed 1 Feb 2000
Application09/918,849Continuation in part · filed 31 Jul 2001
Application10/157,791Continuation in part · filed 28 May 2002
US 2002/0176861 A1Published application
US 6,290,973 B1Related patent
US 6,551,600 B2Related patent
US 2004/0006242 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A method of inducing or stimulating an immune response in a subject comprising administering an effective amount of a compound of the formula I, II, or III, as the active ingredient:

291
Wherein for each of formula I, II, or III:
R1 is selected from the group consisting of
(a) C(O);
(b) C(O)—C1-14 alkyl-C(O), wherein said C1-14 alkyl is optionally substituted with hydroxy, C1-5 alkoxy, C1-5 alkylenedioxy, C1-5 alkylamino, or C1-5-alkyl-aryl, wherein said aryl moiety of said C1-15-alkyl-aryl is optionally substituted with C1-5 alkoxy, C1-5 alkyl amino, C1-5 alkoxy-amino, C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C(O)—C1-5 alkyl C(O)OH, —O—C-1-5 alkylamino-C(O)—C1-5 alkyl-C(O)—C1-5 alkyl;
(c) C2 to C15 straight or branched chain alkyl optionally substituted with hydroxy or alkoxy;
and
(d) —C(O)—C6-12 arylene-C(O)— wherein said arylene is optionally substituted with hydroxy, halogen, nitro or armno;
a and b are independently 0, 1, 2, 3 or 4;
d, d′, d″, e, e′ and e″ are independently an integer from 1 to 4;
X1, X2, Y1 and Y2 are independently selected from the group consisting of null, oxygen, NH and N(C(O)C1-4 alkyl), and N(C1-4 alkyl)2;
W1 and W2 are independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R2 and R5 are independently selected from the group consisting of:
(a) C2 to C20 straight chain or branched chain alkyl which is optionally substituted with oxo, hydroxy or alkoxy,
(b) C2 to C20 straight chain or branched chain alkenyl or dialkenyl which is optionally substituted with oxo, hydroxy or alkoxy;
(c) C2 to C20 straight chain or branched chain alkoxy which is optionally substituted with oxo, hydroxy or alkoxy;
(d) —NH—C2 to C20 straight chain or branched chain alkyl, wherein said alkyl group is optionally substituted with oxo, hydroxy or alkoxy;
and
(e)
292
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R1 and R6 are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl or alkenyl optionally substituted with oxo or fluoro;
R4 and R7 are independently selected from the group consisting of C(O)C2 to C20 straight chain or branched chain alkyl or alkenyl;
C2 to C20 straight chain or branched chain alkyl;
C2 to C20 straight chain or branched chain alkoxy;
C2 to C20 straight chain or branched chain alkenyl;
wherein said alkyl, alkenyl or alkoxy groups can be independently and optionally substituted with hydroxy, fluoro or C1 to C5 alkoxy;
G1, G2, G3 and G4 are independently selected from the group consisting of oxygen, methylene, amino, thiol, —NHC(O)—, and —N(C(O)C1-4 alkyl)—;
or G2R4 or G4R7 may together be a hydrogen atom or hydroxyl;
or a pharmaceutically acceptable salt thereof;
and wherein for Formula II:
a′ and b′ are independently 2, 3, 4, 5, 6, 7, or 8, preferably 2;
Z1 is selected from the group consisting of —OP(O)(OH)2, —P(O)(OH)2,—OP(O)(OR8)(OH) where R8is a C1-C4 alkyl chain, —OS(O)2OH,—S(O)2OH—,—CO2H, —OB(OH)2, —OH, —CH3, —NH2, NR93 where R9 is a C1-C4 alkyl chain;
Z2 is —OP(O)(OH)2, —P(O)(OH)2′, —OP(O)(OR10)(OH) where R10 is a C1-C4 alkyl chain, —OS (O)2OH,—S(O)2OH, CO2H, —OB(OH)2, —OH, CH3, —NH2, —NR11, where R11 is a C1-C4 alkyl chain;
and wherein for Formula 3:
R12 is selected from H and a C1-C4 alkyl chain;
or a pharmaceutical salt thereof,
with the proviso that the compounds of formula I, II, or III are not
293

36 more elements

Facts

Application

10/157,791Filed 28 May 2002

Priority

1 Feb 1999

Published

8 Jan 2004

Term ends

Not estimatedThe source records don’t support an estimate.

Classification35 codes

A61K 39/39
Medicinal preparations containing antigens or antibodies: characterised by the immunostimulating additives, e.g. chemical adjuvants
A61K 31/16
Medicinal preparations containing organic active ingredients: amides, e.g. hydroxamic acids
A61K 31/17
Amides, e.g. hydroxamic acids: having the group >N—C—N< or >N—C—N<, e.g. urea, thiourea, carmustine
A61K 31/6615
Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos: compounds having two or more…

Family

Application60/118,131Us provisional application · filed 1 Feb 1999

Application09/496,152Continuation in part · filed 1 Feb 2000

Application09/918,849Continuation in part · filed 31 Jul 2001

Application10/157,791Continuation in part · filed 28 May 2002

US 2002/0176861 A1Published application

US 6,290,973 B1Related patent

US 6,551,600 B2Related patent

US 2004/0006242 A1This patent

From the US filing history. Foreign family members aren’t listed.